Next Article in Journal
Carnosic Acid Induces Apoptosis and Inhibits Akt/mTOR Signaling in Human Gastric Cancer Cell Lines
Next Article in Special Issue
How Much Protoporphyrin IX Must Be Activated to Obtain Full Efficacy of Methyl Aminolevulinate Photodynamic Therapy? Implication for Treatment Modifications
Previous Article in Journal
Luteal Support with very Low Daily Dose of Human Chorionic Gonadotropin after Fresh Embryo Transfer as an Alternative to Cycle Segmentation for High Responders Patients Undergoing Gonadotropin-Releasing Hormone Agonist-Triggered IVF
Previous Article in Special Issue
Photophysical Properties of Protoporphyrin IX, Pyropheophorbide-a, and Photofrin® in Different Conditions
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceuticals
Volume 14
Issue 3
10.3390/ph14030229
pharmaceuticals-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Systematic Review and Meta-Analysis of In Vitro Anti-Human Cancer Experiments Investigating the Use of 5-Aminolevulinic Acid (5-ALA) for Photodynamic Therapy

by
Yo Shinoda
*,
Daitetsu Kato
,
Ryosuke Ando
,
Hikaru Endo
,
Tsutomu Takahashi
,
Yayoi Tsuneoka
and
Yasuyuki Fujiwara
*
Department of Environmental Health, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2021, 14(3), 229; https://doi.org/10.3390/ph14030229
Submission received: 10 February 2021 / Revised: 26 February 2021 / Accepted: 27 February 2021 / Published: 7 March 2021
(This article belongs to the Special Issue Photodynamic Therapy 2021)
Browse Figures
Versions Notes

Abstract

:
5-Aminolevulinic acid (5-ALA) is an amino acid derivative and a precursor of protoporphyrin IX (PpIX). The photophysical feature of PpIX is clinically used in photodynamic diagnosis (PDD) and photodynamic therapy (PDT). These clinical applications are potentially based on in vitro cell culture experiments. Thus, conducting a systematic review and meta-analysis of in vitro 5-ALA PDT experiments is meaningful and may provide opportunities to consider future perspectives in this field. We conducted a systematic literature search in PubMed to summarize the in vitro 5-ALA PDT experiments and calculated the effectiveness of 5-ALA PDT for several cancer cell types. In total, 412 articles were identified, and 77 were extracted based on our inclusion criteria. The calculated effectiveness of 5-ALA PDT was statistically analyzed, which revealed a tendency of cancer-classification-dependent sensitivity to 5-ALA PDT, and stomach cancer was significantly more sensitive to 5-ALA PDT compared with cancers of different origins. Based on our analysis, we suggest a standardized in vitro experimental protocol for 5-ALA PDT.

1. Introduction

5-Aminolevulinic acid (5-ALA) is a naturally occurring amino acid derivative that acts as a precursor of protoporphyrin IX (PpIX) [1,2,3]. 5-ALA administration to animals, including humans, leads to the synthesis of PpIX, especially in tumors [4,5,6,7]. PpIX is activated by violet light (405 nm) or orange-red light (635 nm), subsequently emitting red fluorescence (620–710 nm) or generating reactive oxygen species (ROS) [8]. These features can potentially be used to visualize or kill cancer. Specifically, 5-ALA has been clinically tested for photodynamic diagnosis (PDD) during surgery to visualize cancer cells by fluorescence and photodynamic therapy (PDT) to target unfavorable neoplasms by increasing ROS production [9,10]. To date, 5-ALA has been clinically approved by the U.S. Food and Drug Administration (FDA) as GLEOLAN® (GLIOLAN® according to the European Medicines Agency (EMA)) for PDD for malignant glioma, and LEVULAN® and AMELUZ® have been approved for the PDT of patients with actinic keratoses. However, there are no FDA- or EMA-approved applications of 5-ALA-PDT for cancer.
Clinical anti-cancer applications of 5-ALA-PDT have been widely reported for several organs, such as the brain [11,12,13,14,15,16], skin [17,18,19,20,21,22,23], pharynx [24], blood and lymph [25], esophagus [26], urethra and prostate [27], and uterus [28]. In addition, 97 clinical trials of 5-ALA PDT for cancer treatment have been registered in the U.S. National Library of Medicine (ClinicalTrials.gov) as of 10 March 2021. Therefore, 5-ALA will hopefully be approved in the near future as a PDT drug for cancer patients. These clinical trials and applications are based on in vivo animal experiments, and these animal experiments are based on in vitro cell culture experiments. For the clinical application of 5-ALA PDT in cancer, a comprehensive review of in vitro 5-ALA PDT experiments and analysis of these results are meaningful and may provide important opportunities to consider for the future direction of 5-ALA experiments and clinical trials.
In this study, we systematically extracted and listed in vitro experiments that investigated 5-ALA PDT. We also performed a meta-analysis of these data by calculating and comparing the effectiveness of 5-ALA PDT in several cancer cell types from each article. Finally, we suggest a standard experimental protocol for the validation of future in vitro 5-ALA PDT experiments.

2. Methods

2.1. Literature Search and Selection

A systematic literature review using PubMed was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement (PRISMA) guidelines [29]. For the title or abstract search, we used the term sets [5-aminolevulinic acid, aminolevulinic acid, dALA, δALA, 5-ALA, 5ALA], [in vitro, culture], and [photodynamic therapy, PDT] for OR searching in each term set, and each term set was used together for AND searching. In addition, the publication date was limited to the beginning of 1900 to the end of 2019 (available online). Together, the search query used was ((aminolevulinic acid [Title/Abstract] OR aminolevulinic acid [Title/Abstract] OR dALA [Title/Abstract] OR δALA [Title/Abstract] OR 5-ALA [Title/Abstract] OR 5ALA [Title/Abstract]) AND (in vitro [Title/Abstract] OR culture [Title/Abstract]) AND (photodynamic therapy [Title/Abstract] OR PDT [Title/Abstract])) AND (1900/01/01 [Date-Publication]: 2019/12/31 [Date-Publication]). The searched articles were further selected based on whether they included all of the following information: cell name, fluence, irradiation wavelength, time of incubation with 5-ALA, duration between 5-ALA treatment and irradiation, and duration between irradiation and viability assays. The selected articles that described the median lethal concentration (LC50) in the text or those in which the LC50 could be estimated and/or calculated from the table or graph were included. Estimated LC50 and fluence from graphs were rounded.

2.2. Consistency of Terminology

Some papers used different terms to express the same thing. In addition, some standardizations of different terms were required to perform statistical analysis. Therefore, some terminologies were unified as follows: astrocytoma was used as glioblastoma, glioma stem-like cell was used as glioma stem cell, and glioblastoma stem-like cell was used as glioblastoma stem cell.

2.3. Data Collection, Processing, and Statistics

For data comparisons, the effectiveness of each application was calculated by the reciprocal of the fluence multiplied by the LC50 (cm2/(J·µM)). This effectiveness is thought to be proportional to the sensitivity of the cell to 5-ALA PDT. If there were more than three articles that used the same classified cells or cells from the same organ, similar wavelengths for irradiation (around 635 nm), the same duration of 5-ALA incubation (4 h), and the same duration between irradiation and viability assays (24 h), the values of effectiveness were averaged and assessed by one-way analysis of variance (ANOVA) with the post hoc Tukey–Kramer test using Statcel2 software (Seiunsha, Tokyo, Japan). If the sample size was greater than six, the data were assessed by the Wilcoxon rank-sum test using JMP Pro software (SAS Institute Japan, Tokyo, Japan).

3. Results

3.1. Collection of In Vitro 5-ALA PDT Experiments

The initial search resulted in 412 articles, of which 77 articles met the inclusion criteria mentioned in the Methods section. These articles included a total of 146 in vitro viability assays of cells treated with PDT under different conditions. They included 116, 12, 9, and 9 viability assays for cell lines derived from humans, mice, rats, and canines, respectively. The PDT experiments using human cell lines are listed in Table 1, and the total number of studies was 62. Eighty cell lines from different origins (21 organs) and classifications (16 classes) were tested. Brain cancer and adenocarcinoma were the most tested cancer origin and classification, respectively. Overall, several different experimental conditions were adapted in each study, including various durations of incubation with 5-ALA, irradiation wavelengths, fluences, and durations between irradiation and viability assays. Therefore, it was difficult to directly compare these experimental results. To ensure the comparability of the results, we extracted the data from studies that used similar experimental conditions (irradiation wavelength, duration of 5-ALA incubation, and duration between irradiation and viability assays). Then, we roughly estimated the effectiveness of 5-ALA PDT for different cells using the following equation. The effectiveness is the new parameter we introduced, which is thought to correlate to the sensitivity of the cells to 5-ALA PDT because both LC50 and fluence parameters are roughly inversely proportional to the sensitivity of the cells in PDT experiments [30,31].
E f f e c t i v e n e s s = 1 L C 50 × F l u e n c e c m 2 / J · µ M
The effectiveness indicates the extent of 5-ALA effects on the treated cells under the individual experimental conditions. The larger the effectiveness value, the more effective 5-ALA PDT was against the cell. Although there were different effectiveness values estimated for the same cell types in different papers (such as 0.1 to 1,131.9 for A431 cells), most results showed a similar range of effectiveness values.

3.2. 5-ALA PDT Effect on Cells of Different Cancer Classifications

The effectiveness against cells of the same cancer classifications was averaged and compared with each class (Figure 1). Several reports showed that the feature of the cells was altered by their microenvironments, such as 2D monolayer culture or 3D aggregation-forming spheres [90,91,92,93]. In the present review, because the inclusion and exclusion of the data from sphere cultures did not show any statistical differences, all of the data were included and averaged. Although there were no statistical significances, adenocarcinoma, glioblastoma stem cell (GSC), and glioma stem cell tended to show higher effectiveness values than squamous cell carcinoma (SCC), glioblastoma, and carcinoma, which may suggest that the effects of 5-ALA PDT are cancer-classification-dependent.

3.3. 5-ALA PDT Effect on Cells of Different Cancer Origins

Next, the effectiveness against cells of the same cancer origin was averaged and compared with each origin (Figure 2). Because the inclusion and exclusion of the data from sphere cultures and outliers did not show any statistical differences, all of the data were included and averaged. As a result, the stomach was identified as the organ most affected by 5-ALA PDT. Among the other organs, there were no statistically significant differences. However, the number of experiments using stomach-derived cells (n = 3) was small, and these experiments were performed in the same study. Therefore, this result should be considered carefully.

4. Discussion and Future Perspective

In the present review, we summarized past and recent (until the end of 2019) in vitro experiments investigating 5-ALA PDT for cancer cells and compared these data by calculating the effectiveness value. In total, 116 in vitro assays for human cancer cells were extracted, including cancer cells from 21 origins and 16 cancer classifications. Effectiveness values were calculated from the LC50 and fluence to compare the sensitivity of each cancer cell type to 5-ALA PDT. These data suggest that there are some tendencies of sensitivity to 5-ALA PDT in cells of different origins and classifications.
Several potential mechanisms may contribute to the differences in the sensitivity of each origin and classification to 5-ALA PDT. The most important candidate that influences the PDT sensitivity is the protein family associated with redox reactions. Oxidative stress-related proteins, such as superoxide dismutase [94], catalase [95], and NO synthase [96], are reported to affect PDT sensitivity. Glutathione and related proteins, such as glutathione peroxidase, glutathione-S-transferase, glutathione transferase omega-1, and glutathione synthase, are also thought to be associated with cell resistance to PDT [94,97,98]. Heme oxygenase-1 (HO-1) is an inducible cytoprotective enzyme that protects cells from oxidative stress, and its expression is induced by PDT [99]. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) regulates cell responses to oxidative stress, which affects the PDT sensitivity [100]. The NAD(P)H/FAD redox status has been reported to affect PDT sensitivity [101]. The expression levels of these redox-related proteins, peptides, and compounds can be altered in cancer cells and may influence their sensitivity to 5-ALA PDT.
Several papers have reported the anti-cancer property of 5-ALA PDT; however, most articles do not describe all of the experimental protocols, preventing reproducibility. Although similar problems occur and should be considered in all manuscripts, it is still important for authors to describe their detailed experimental protocols to ensure reproducibility by other researchers and for reviewers to carefully assess the manuscripts. For the in vitro PDT experiments, complete chemical formulation of 5-ALA (such as 5-ALA hydrochloride) should be described, not 5-ALA alone; otherwise, the dimerization is reported [102]. Moreover, the parameters we mention in Table 1 (cell name, duration of incubation, irradiation wavelength, fluence, and duration between irradiation and viability assays) should be clearly mentioned in Section 2 because all of these parameters possibly affect the sensitivity of cells to 5-ALA PDT and the results of cell viability assays. Comparisons of the duration of 5-ALA incubation [35,68,103], irradiation wavelength [104,105], and fluence [30,31] showed that each parameter strongly affected cell viability. In addition, the duration between irradiation and viability assays can also affect the results because cell proliferation after light irradiation can be influenced by the number of viable cells with a sigmoid shape.
In this review, we compared the effectiveness calculated from the LC50 and fluence. The calculated effectiveness may be a useful parameter to compare the sensitivity of cells to 5-ALA PDT among individual manuscripts; however, it has some limitations to consider. Although both LC50 and fluence parameters are roughly inversely proportional to the sensitivity of the cells in PDT experiments, this inverse relationship (especially for fluence) does not show absolute linearity [31]. Based on our calculation, high fluence usually showed a relatively high effectiveness [30,57,106,107]. Therefore, the calculated effectiveness may be overestimated in the experiments using high fluence. The cellular microenvironments, such as 2D or 3D culture, are also possible candidates that may affect 5-ALA PDT sensitivity. Therefore, 2D/3D comparisons might be required. In this manuscript, the inclusion and exclusion of 3D culture data did not show any statistical changes, but this might be caused by the small number of datasets. We discarded several potential parameters that may affect in vitro PDT assays, such as the components of 5-ALA (hydrochloric acid, nitrate, and phosphate), initial cell density, light source (laser, lamp (halogen, mercury, or xenon), or LED), light irradiance, wash conditions, and completeness of light shielding except for light irradiation. These parameters can also affect the PDT results. For example, the value of light irradiance strongly influences cell viability [105,108,109]. Therefore, especially for the reproducibility, these parameters should be described in the individual manuscript together with the parameters described above.
For the meta-analysis and data comparison between each report, the experimental procedure for in vitro 5-ALA PDT experiments should be standardized as much as possible. We propose a standardized protocol developed with reference to papers listed in Table 1 (Scheme 1), and a similar protocol for investigating 5-ALA PDT in breast cancer cells has been recommended previously [110]. This protocol is for in vitro 5-ALA PDT experiments, but it can potentially be used for other in vitro PDT experiments using different photosensitizers with some modifications. The steps of this protocol are culturing cells to ~80% confluency, incubating cells with 5-ALA for 4 h, irradiating immediately after providing cells with fresh medium, and performing the viability assay 24 h after irradiation. A cell confluency of approximately 80% should be used for prevention of the effect of contact inhibition (including initiation of cell cycle arrest, downregulation of proliferation, and mitogen signaling pathways) [111]. It has been reported that a 4 h incubation time of 5-ALA is usually sufficient to induce maximal PDT effect for several cancer cells [60,65,112]. In addition, many studies including the references in this review used 4 h for their general experimental condition. However, some cells and experimental conditions require the incubation time of 5-ALA to be more than 4 h [62,85,107,113] and the time may also be affected by the 5-ALA concentration [35]. The timing of irradiation should be performed immediately after washout of 5-ALA because intracellular concentration of PpIX is gradually reduced after washout by cell metabolism [114]. We hope that this standardized protocol may help researchers conducting 5-ALA (or other photosensitizer) PDT experiments.
More in vitro and in vivo 5-ALA PDT experiments for cancer should be performed to facilitate the clinical application of 5-ALA PDT in the future. In addition, 81 clinical trials have been registered in the U.S. National Library of Medicine. There are potential risks and side effects that should be considered during these trials and experiments; however, these efforts might advance the development of novel clinical approaches for the treatment of several cancers. To expand 5-ALA applications for several cancers, further in vitro 5-ALA PDT experiments are still required and should be continued.

Author Contributions

Conceptualization, Y.S.; methodology and validation, Y.S., T.T., and Y.T.; investigation, Y.S., D.K., R.A., and H.E.; writing—original draft preparation, Y.S.; writing—review and editing, Y.S., T.T., Y.T., and Y.F.; supervision, Y.S. and Y.F.; project administration, Y.S.; funding acquisition, Y.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by a grant from the Institute for Social Medicine at Tokyo Univ. of Pharm. and Life Sci. (2018 and 2019 to Y.S.), the Shimabara Science Promotion Foundation (2017 to Y.S.), and GSK Japan (2015 to Y.S.).

Acknowledgments

We gratefully acknowledge Eisuke Enoki for his clinical advice.

Conflicts of Interest

The authors declare no competing financial interest.

References

  1. Berlin, N.I.; Neuberger, A.; Scott, J.J. The metabolism of delta -aminolaevulic acid. 1. Normal pathways, studied with the aid of 15N. Biochem. J. 1956, 64, 80–90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Berlin, N.I.; Neuberger, A.; Scott, J.J. The metabolism of delta -aminolaevulic acid. 2. Normal pathways, studied with the aid of 14C. Biochem. J. 1956, 64, 90–100. [Google Scholar] [CrossRef] [Green Version]
  3. Fukuda, H.; Casas, A.; Batlle, A. Aminolevulinic acid: From its unique biological function to its star role in photodynamic therapy. Int. J. Biochem. Cell Biol. 2005, 37, 272–276. [Google Scholar] [CrossRef]
  4. Kennedy, J.C.; Pottier, R.H. Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. J. Photochem. Photobiol. B 1992, 14, 275–292. [Google Scholar] [CrossRef]
  5. Kennedy, J.C.; Pottier, R.H.; Pross, D.C. Photodynamic therapy with endogenous protoporphyrin IX: Basic principles and present clinical experience. J. Photochem. Photobiol. B 1990, 6, 143–148. [Google Scholar] [CrossRef]
  6. Krieg, R.C.; Messmann, H.; Rauch, J.; Seeger, S.; Knuechel, R. Metabolic characterization of tumor cell-specific protoporphyrin IX accumulation after exposure to 5-aminolevulinic acid in human colonic cells. Photochem. Photobiol. 2002, 76, 518–525. [Google Scholar] [CrossRef]
  7. Zenzen, V.; Zankl, H. Protoporphyrin IX-accumulation in human tumor cells following topical ALA- and h-ALA-application in vivo. Cancer Lett. 2003, 202, 35–42. [Google Scholar] [CrossRef] [PubMed]
  8. Berg, K.; Selbo, P.K.; Weyergang, A.; Dietze, A.; Prasmickaite, L.; Bonsted, A.; Engesaeter, B.O.; Angell-Petersen, E.; Warloe, T.; Frandsen, N.; et al. Porphyrin-related photosensitizers for cancer imaging and therapeutic applications. J. Microsc. 2005, 218, 133–147. [Google Scholar] [CrossRef] [PubMed]
  9. Casas, A. Clinical uses of 5-aminolaevulinic acid in photodynamic treatment and photodetection of cancer: A review. Cancer Lett. 2020, 490, 165–173. [Google Scholar] [CrossRef] [PubMed]
  10. Ishizuka, M.; Abe, F.; Sano, Y.; Takahashi, K.; Inoue, K.; Nakajima, M.; Kohda, T.; Komatsu, N.; Ogura, S.; Tanaka, T. Novel development of 5-aminolevurinic acid (ALA) in cancer diagnoses and therapy. Int. Immunopharmacol. 2011, 11, 358–365. [Google Scholar] [CrossRef]
  11. Mahmoudi, K.; Garvey, K.L.; Bouras, A.; Cramer, G.; Stepp, H.; Jesu Raj, J.G.; Bozec, D.; Busch, T.M.; Hadjipanayis, C.G. 5-aminolevulinic acid photodynamic therapy for the treatment of high-grade gliomas. J. Neurooncol. 2019, 141, 595–607. [Google Scholar] [CrossRef] [PubMed]
  12. Cramer, S.W.; Chen, C.C. Photodynamic Therapy for the Treatment of Glioblastoma. Front. Surg. 2020, 6, 81. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Friesen, S.A.; Hjortland, G.O.; Madsen, S.J.; Hirschberg, H.; Engebraten, O.; Nesland, J.M.; Peng, Q. 5-Aminolevulinic acid-based photodynamic detection and therapy of brain tumors (review). Int. J. Oncol. 2002, 21, 577–582. [Google Scholar] [CrossRef]
  14. Stepp, H.; Stummer, W. 5-ALA in the management of malignant glioma. Lasers Surg. Med. 2018, 50, 399–419. [Google Scholar] [CrossRef] [Green Version]
  15. Nordmann, N.J.; Michael, A.P. 5-Aminolevulinic acid radiodynamic therapy for treatment of high-grade gliomas: A systematic review. Clin. Neurol. Neurosurg. 2020, 201, 106430. [Google Scholar] [CrossRef]
  16. Tetard, M.C.; Vermandel, M.; Mordon, S.; Lejeune, J.P.; Reyns, N. Experimental use of photodynamic therapy in high grade gliomas: A review focused on 5-aminolevulinic acid. Photodiagnosis Photodyn. Ther. 2014, 11, 319–330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Champeau, M.; Vignoud, S.; Mortier, L.; Mordon, S. Photodynamic therapy for skin cancer: How to enhance drug penetration? J. Photochem. Photobiol. B 2019, 197, 111544. [Google Scholar] [CrossRef]
  18. Blume, J.E.; Oseroff, A.R. Aminolevulinic acid photodynamic therapy for skin cancers. Dermatol. Clin. 2007, 25, 5–14. [Google Scholar] [CrossRef]
  19. Naidoo, C.; Kruger, C.A.; Abrahamse, H. Simultaneous Photodiagnosis and Photodynamic Treatment of Metastatic Melanoma. Molecules 2019, 24, 3153. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Zou, Y.; Zhao, Y.; Yu, J.; Luo, X.; Han, J.; Ye, Z.; Li, J.; Lin, H. Photodynamic therapy versus surgical excision to basal cell carcinoma: Meta-analysis. J. Cosmet. Dermatol. 2016, 15, 374–382. [Google Scholar] [CrossRef]
  21. Marmur, E.S.; Schmults, C.D.; Goldberg, D.J. A review of laser and photodynamic therapy for the treatment of nonmelanoma skin cancer. Dermatol. Surg. 2004, 30, 264–271. [Google Scholar] [CrossRef] [PubMed]
  22. Zeitouni, N.C.; Oseroff, A.R.; Shieh, S. Photodynamic therapy for nonmelanoma skin cancers. Current review and update. Mol. Immunol. 2003, 39, 1133–1136. [Google Scholar] [CrossRef]
  23. De Vijlder, H.C.; Middelburg, T.; De Bruijn, H.S.; Martino Neumann, H.A.; Sterenborg, H.C.; Robinson, D.J.; De Haas, E.R. Optimizing ALA-PDT in the management of non-melanoma skin cancer by fractionated illumination. G. Ital. Dermatol. Venereol. 2009, 144, 433–439. [Google Scholar] [PubMed]
  24. Jin, X.; Xu, H.; Deng, J.; Dan, H.; Ji, P.; Chen, Q.; Zeng, X. Photodynamic therapy for oral potentially malignant disorders. Photodiagnosis Photodyn. Ther. 2019, 28, 146–152. [Google Scholar] [CrossRef]
  25. Oka, T.; Matsuoka, K.I.; Utsunomiya, A. Sensitive Photodynamic Detection of Adult T-cell Leukemia/Lymphoma and Specific Leukemic Cell Death Induced by Photodynamic Therapy: Current Status in Hematopoietic Malignancies. Cancers 2020, 12, 335. [Google Scholar] [CrossRef] [Green Version]
  26. Gross, S.A.; Wolfsen, H.C. The role of photodynamic therapy in the esophagus. Gastrointest. Endosc. Clin. N. Am. 2010, 20, 35–53. [Google Scholar] [CrossRef]
  27. Fukuhara, H.; Yamamoto, S.; Karashima, T.; Inoue, K. Photodynamic diagnosis and therapy for urothelial carcinoma and prostate cancer: New imaging technology and therapy. Int. J. Clin. Oncol. 2021, 26, 18–25. [Google Scholar] [CrossRef]
  28. Matoba, Y.; Banno, K.; Kisu, I.; Aoki, D. Clinical application of photodynamic diagnosis and photodynamic therapy for gynecologic malignant diseases: A review. Photodiagnosis Photodyn. Ther. 2018, 24, 52–57. [Google Scholar] [CrossRef]
  29. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e1000097. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Berlanda, J.; Kiesslich, T.; Engelhardt, V.; Krammer, B.; Plaetzer, K. Comparative in vitro study on the characteristics of different photosensitizers employed in PDT. J. Photochem. Photobiol. B 2010, 100, 173–180. [Google Scholar] [CrossRef] [PubMed]
  31. Hartl, B.A.; Hirschberg, H.; Marcu, L.; Cherry, S.R. Characterizing low fluence thresholds for in vitro photodynamic therapy. Biomed. Opt. Express 2015, 6, 770–779. [Google Scholar] [CrossRef] [Green Version]
  32. Riesenberg, R.; Fuchs, C.; Kriegmair, M. Photodynamic effects of 5-aminolevulinic acid-induced porphyrin on human bladder carcinoma cells in vitro. Eur. J. Cancer 1996, 32A, 328–334. [Google Scholar] [CrossRef]
  33. Krieg, R.C.; Herr, A.; Raupach, K.; Ren, Q.; Schwamborn, K.; Knuechel, R. Analyzing effects of photodynamic therapy with 5-aminolevulinic acid (ALA) induced protoporphyrin IX (PPIX) in urothelial cells using reverse phase protein arrays. Photochem. Photobiol. Sci. 2007, 6, 1296–1305. [Google Scholar] [CrossRef]
  34. Wild, P.J.; Krieg, R.C.; Seidl, J.; Stoehr, R.; Reher, K.; Hofmann, C.; Louhelainen, J.; Rosenthal, A.; Hartmann, A.; Pilarsky, C.; et al. RNA expression profiling of normal and tumor cells following photodynamic therapy with 5-aminolevulinic acid-induced protoporphyrin IX in vitro. Mol. Cancer Ther. 2005, 4, 516–528. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Cornelius, J.F.; Eismann, L.; Ebbert, L.; Senger, B.; Petridis, A.K.; Kamp, M.A.; Sorg, R.V.; Steiger, H.J. 5-Aminolevulinic acid-based photodynamic therapy of chordoma: In vitro experiments on a human tumor cell line. Photodiagnosis Photodyn. Ther. 2017, 20, 111–115. [Google Scholar] [CrossRef] [PubMed]
  36. Yanase, S.; Nomura, J.; Matsumura, Y.; Nagai, K.; Kinoshita, M.; Nakanishi, H.; Ohnishi, Y.; Tokuda, T.; Tagawa, T. Enhancement of the effect of 5-aminolevulinic acid-based photodynamic therapy by simultaneous hyperthermia. Int. J. Oncol. 2005, 27, 193–201. [Google Scholar] [CrossRef]
  37. Nomura, J.; Yanase, S.; Tokuda, T.; Matsumura, Y.; Sekida, M.; Tagawa, T. Griseofulvin enhances the effect of aminolevulinic acid-based photodynamic therapy in vitro. Photomed. Laser Surg. 2006, 24, 186–191. [Google Scholar] [CrossRef] [PubMed]
  38. Schwake, M.; Nemes, A.; Dondrop, J.; Schroeteler, J.; Schipmann, S.; Senner, V.; Stummer, W.; Ewelt, C. In-Vitro Use of 5-ALA for Photodynamic Therapy in Pediatric Brain Tumors. Neurosurgery 2018, 83, 1328–1337. [Google Scholar] [CrossRef]
  39. Shi, L.; Buchner, A.; Pohla, H.; Pongratz, T.; Ruhm, A.; Zimmermann, W.; Gederaas, O.A.; Zhang, L.; Wang, X.; Stepp, H.; et al. Methadone enhances the effectiveness of 5-aminolevulinic acid-based photodynamic therapy for squamous cell carcinoma and glioblastoma in vitro. J. Biophotonics 2019, 12, e201800468. [Google Scholar] [CrossRef] [PubMed]
  40. Hirschberg, H.; Sun, C.H.; Tromberg, B.J.; Yeh, A.T.; Madsen, S.J. Enhanced cytotoxic effects of 5-aminolevulinic acid-mediated photodynamic therapy by concurrent hyperthermia in glioma spheroids. J. Neurooncol. 2004, 70, 289–299. [Google Scholar] [CrossRef] [Green Version]
  41. Fahey, J.M.; Emmer, J.V.; Korytowski, W.; Hogg, N.; Girotti, A.W. Antagonistic Effects of Endogenous Nitric Oxide in a Glioblastoma Photodynamic Therapy Model. Photochem. Photobiol. 2016, 92, 842–853. [Google Scholar] [CrossRef] [Green Version]
  42. Albert, I.; Hefti, M.; Luginbuehl, V. Physiological oxygen concentration alters glioma cell malignancy and responsiveness to photodynamic therapy in vitro. Neurol. Res. 2014, 36, 1001–1010. [Google Scholar] [CrossRef]
  43. Schimanski, A.; Ebbert, L.; Sabel, M.C.; Finocchiaro, G.; Lamszus, K.; Ewelt, C.; Etminan, N.; Fischer, J.C.; Sorg, R.V. Human glioblastoma stem-like cells accumulate protoporphyrin IX when subjected to exogenous 5-aminolaevulinic acid, rendering them sensitive to photodynamic treatment. J. Photochem. Photobiol. B 2016, 163, 203–210. [Google Scholar] [CrossRef]
  44. Fisher, C.J.; Niu, C.; Foltz, W.; Chen, Y.; Sidorova-Darmos, E.; Eubanks, J.H.; Lilge, L. ALA-PpIX mediated photodynamic therapy of malignant gliomas augmented by hypothermia. PLoS ONE 2017, 12, e0181654. [Google Scholar] [CrossRef] [Green Version]
  45. Fisher, C.; Obaid, G.; Niu, C.; Foltz, W.; Goldstein, A.; Hasan, T.; Lilge, L. Liposomal Lapatinib in Combination with Low-Dose Photodynamic Therapy for the Treatment of Glioma. J. Clin. Med. 2019, 8, 2214. [Google Scholar] [CrossRef] [Green Version]
  46. Ritz, R.; Scheidle, C.; Noell, S.; Roser, F.; Schenk, M.; Dietz, K.; Strauss, W.S. In vitro comparison of hypericin and 5-aminolevulinic acid-derived protoporphyrin IX for photodynamic inactivation of medulloblastoma cells. PLoS ONE 2012, 7, e51974. [Google Scholar] [CrossRef] [Green Version]
  47. Hefti, M.; Albert, I.; Luginbuehl, V. Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells. J. Neurooncol. 2012, 108, 443–450. [Google Scholar] [CrossRef] [PubMed]
  48. Sailer, R.; Strauss, W.S.; Wagner, M.; Emmert, H.; Schneckenburger, H. Relation between intracellular location and photodynamic efficacy of 5-aminolevulinic acid-induced protoporphyrin IX in vitro. Comparison between human glioblastoma cells and other cancer cell lines. Photochem. Photobiol. Sci. 2007, 6, 145–151. [Google Scholar] [CrossRef] [PubMed]
  49. Cornelius, J.F.; Slotty, P.J.; El Khatib, M.; Giannakis, A.; Senger, B.; Steiger, H.J. Enhancing the effect of 5-aminolevulinic acid based photodynamic therapy in human meningioma cells. Photodiagnosis Photodyn. Ther. 2014, 11, 1–6. [Google Scholar] [CrossRef] [PubMed]
  50. Wu, S.M.; Ren, Q.G.; Zhou, M.O.; Peng, Q.; Chen, J.Y. Protoporphyrin IX production and its photodynamic effects on glioma cells, neuroblastoma cells and normal cerebellar granule cells in vitro with 5-aminolevulinic acid and its hexylester. Cancer Lett. 2003, 200, 123–131. [Google Scholar] [CrossRef]
  51. Fahey, J.M.; Girotti, A.W. Nitric oxide-mediated resistance to photodynamic therapy in a human breast tumor xenograft model: Improved outcome with NOS2 inhibitors. Nitric Oxide 2017, 62, 52–61. [Google Scholar] [CrossRef] [Green Version]
  52. Calvo, G.; Saenz, D.; Simian, M.; Sampayo, R.; Mamone, L.; Vallecorsa, P.; Batlle, A.; Casas, A.; Di Venosa, G. Reversal of the Migratory and Invasive Phenotype of Ras-Transfected Mammary Cells by Photodynamic Therapy Treatment. J. Cell. Biochem. 2017, 118, 464–477. [Google Scholar] [CrossRef]
  53. Ziegler, V.G.; Knaup, J.; Stahl, D.; Krammer, B.; Plaetzer, K. Fluorescence detection and depletion of T47D breast cancer cells from human mononuclear cell-enriched blood preparations by photodynamic treatment: Basic in vitro experiments towards the removal of circulating tumor cells. Lasers Surg. Med. 2011, 43, 548–556. [Google Scholar] [CrossRef]
  54. Krieg, R.C.; Messmann, H.; Schlottmann, K.; Endlicher, E.; Seeger, S.; Scholmerich, J.; Knuechel, R. Intracellular localization is a cofactor for the phototoxicity of protoporphyrin IX in the gastrointestinal tract: In vitro study. Photochem. Photobiol. 2003, 78, 393–399. [Google Scholar] [CrossRef]
  55. Hatakeyama, T.; Murayama, Y.; Komatsu, S.; Shiozaki, A.; Kuriu, Y.; Ikoma, H.; Nakanishi, M.; Ichikawa, D.; Fujiwara, H.; Okamoto, K.; et al. Efficacy of 5-aminolevulinic acid-mediated photodynamic therapy using light-emitting diodes in human colon cancer cells. Oncol. Rep. 2013, 29, 911–916. [Google Scholar] [CrossRef] [Green Version]
  56. Wawrzyniec, K.; Kawczyk-Krupka, A.; Czuba, Z.P.; Krol, W.; Sieron, A. The influence of ALA-mediated photodynamic therapy on secretion of selected growth factors by colon cancer cells in hypoxia-like environment in vitro. Photodiagnosis Photodyn. Ther. 2015, 12, 598–611. [Google Scholar] [CrossRef] [PubMed]
  57. Kawczyk-Krupka, A.; Czuba, Z.P.; Kwiatek, B.; Kwiatek, S.; Krupka, M.; Sieron, K. The effect of ALA-PDT under normoxia and cobalt chloride (CoCl2)-induced hypoxia on adhesion molecules (ICAM-1, VCAM-1) secretion by colorectal cancer cells. Photodiagnosis Photodyn. Ther. 2017, 19, 103–115. [Google Scholar] [CrossRef] [PubMed]
  58. Chen, X.; Zhao, P.; Chen, F.; Li, L.; Luo, R. Effect and mechanism of 5-aminolevulinic acid-mediated photodynamic therapy in esophageal cancer. Lasers Med. Sci. 2011, 26, 69–78. [Google Scholar] [CrossRef]
  59. Zhang, X.; Cai, L.; He, J.; Li, X.; Li, L.; Chen, X.; Lan, P. Influence and mechanism of 5-aminolevulinic acid-photodynamic therapy on the metastasis of esophageal carcinoma. Photodiagnosis Photodyn. Ther. 2017, 20, 78–85. [Google Scholar] [CrossRef] [PubMed]
  60. Yang, T.H.; Chen, C.T.; Wang, C.P.; Lou, P.J. Photodynamic therapy suppresses the migration and invasion of head and neck cancer cells in vitro. Oral Oncol. 2007, 43, 358–365. [Google Scholar] [CrossRef] [PubMed]
  61. Ahn, J.C.; Biswas, R.; Mondal, A.; Lee, Y.K.; Chung, P.S. Cisplatin enhances the efficacy of 5-aminolevulinic acid mediated photodynamic therapy in human head and neck squamous cell carcinoma. Gen. Physiol. Biophys. 2014, 33, 53–62. [Google Scholar] [CrossRef]
  62. Yow, C.M.; Wong, C.K.; Huang, Z.; Ho, R.J. Study of the efficacy and mechanism of ALA-mediated photodynamic therapy on human hepatocellular carcinoma cell. Liver. Int. 2007, 27, 201–208. [Google Scholar] [CrossRef]
  63. Vonarx-Coinsman, V.; Foultier, M.T.; de Brito, L.X.; Morlet, L.; Gouyette, A.; Patrice, T. HepG2 human hepatocarcinoma cells: An experimental model for photosensitization by endogenous porphyrins. J. Photochem. Photobiol. B 1995, 30, 201–208. [Google Scholar] [CrossRef]
  64. Campbell, D.L.; Gudgin-Dickson, E.F.; Forkert, P.G.; Pottier, R.H.; Kennedy, J.C. Detection of early stages of carcinogenesis in adenomas of murine lung by 5-aminolevulinic acid-induced protoporphyrin IX fluorescence. Photochem. Photobiol. 1996, 64, 676–682. [Google Scholar] [CrossRef] [PubMed]
  65. Su, G.C.; Wei, Y.H.; Wang, H.W. NADH fluorescence as a photobiological metric in 5-aminolevlinic acid (ALA)-photodynamic therapy. Opt. Express 2011, 19, 21145–21154. [Google Scholar] [CrossRef]
  66. Boehncke, W.H.; Ruck, A.; Naumann, J.; Sterry, W.; Kaufmann, R. Comparison of sensitivity towards photodynamic therapy of cutaneous resident and infiltrating cell types in vitro. Lasers Surg. Med. 1996, 19, 451–457. [Google Scholar] [CrossRef]
  67. Betz, C.S.; Lai, J.P.; Xiang, W.; Janda, P.; Heinrich, P.; Stepp, H.; Baumgartner, R.; Leunig, A. In vitro photodynamic therapy of nasopharyngeal carcinoma using 5-aminolevulinic acid. Photochem. Photobiol. Sci. 2002, 1, 315–319. [Google Scholar] [CrossRef] [PubMed]
  68. Wang, X.; Jin, J.; Li, W.; Wang, Q.; Han, Y.; Liu, H. Differential in vitro sensitivity of oral precancerous and squamous cell carcinoma cell lines to 5-aminolevulinic acid-mediated photodynamic therapy. Photodiagnosis Photodyn. Ther. 2020, 29, 101554. [Google Scholar] [CrossRef] [PubMed]
  69. Teshigawara, T.; Mizuno, M.; Ishii, T.; Kitajima, Y.; Utsumi, F.; Sakata, J.; Kajiyama, H.; Shibata, K.; Ishizuka, M.; Kikkawa, F. Novel potential photodynamic therapy strategy using 5-Aminolevulinic acid for ovarian clear-cell carcinoma. Photodiagnosis Photodyn. Ther. 2018, 21, 121–127. [Google Scholar] [CrossRef] [PubMed]
  70. Chakrabarti, P.; Orihuela, E.; Egger, N.; Neal, D.E., Jr.; Gangula, R.; Adesokun, A.; Motamedi, M. Delta-aminolevulinic acid-mediated photosensitization of prostate cell lines: Implication for photodynamic therapy of prostate cancer. Prostate 1998, 36, 211–218. [Google Scholar] [CrossRef]
  71. Robertson, C.A.; Abrahamse, H.; Evans, D. The in vitro PDT efficacy of a novel metallophthalocyanine (MPc) derivative and established 5-ALA photosensitizing dyes against human metastatic melanoma cells. Lasers Surg. Med. 2010, 42, 766–776. [Google Scholar] [CrossRef] [PubMed]
  72. Cordoba, F.; Braathen, L.R.; Weissenberger, J.; Vallan, C.; Kato, M.; Nakashima, I.; Weis, J.; von Felbert, V. 5-aminolaevulinic acid photodynamic therapy in a transgenic mouse model of skin melanoma. Exp. Dermatol. 2005, 14, 429–437. [Google Scholar] [CrossRef]
  73. Gilmore, B.F.; McCarron, P.A.; Morrow, D.I.; Murphy, D.J.; Woolfson, A.D.; Donnelly, R.F. In vitro phototoxicity of 5-aminolevulinic acid and its methyl ester and the influence of barrier properties on their release from a bioadhesive patch. Eur. J. Pharm. Biopharm. 2006, 63, 295–309. [Google Scholar] [CrossRef]
  74. Novak, B.; Heesen, L.; Schary, N.; Lubbert, H. The influence of different illumination parameters on protoporphyrin IX induced cell death in squamous cell carcinoma cells. Photodiagnosis Photodyn. Ther. 2018, 21, 385–392. [Google Scholar] [CrossRef]
  75. Shi, L.; Wang, X.; Zhao, F.; Luan, H.; Tu, Q.; Huang, Z.; Wang, H.; Wang, H. In vitro evaluation of 5-aminolevulinic acid (ALA) loaded PLGA nanoparticles. Int. J. Nanomed. 2013, 8, 2669–2676. [Google Scholar] [CrossRef] [Green Version]
  76. Liu, H.; Daly, L.; Rudd, G.; Khan, A.P.; Mallidi, S.; Liu, Y.; Cuckov, F.; Hasan, T.; Celli, J.P. Development and evaluation of a low-cost, portable, LED-based device for PDT treatment of early-stage oral cancer in resource-limited settings. Lasers Surg. Med. 2019, 51, 345–351. [Google Scholar] [CrossRef]
  77. Mei, L.H.; Yang, G.; Fang, F. Hyperbaric Oxygen Combined with 5-Aminolevulinic Acid Photodynamic Therapy Inhibited Human Squamous Cell Proliferation. Biol. Pharm. Bull. 2019, 42, 394–400. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Ishida, N.; Watanabe, D.; Akita, Y.; Nakano, A.; Yamashita, N.; Kuhara, T.; Yanagishita, T.; Takeo, T.; Tamada, Y.; Matsumoto, Y. Etretinate enhances the susceptibility of human skin squamous cell carcinoma cells to 5-aminolaevulic acid-based photodynamic therapy. Clin. Exp. Dermatol. 2009, 34, 385–389. [Google Scholar] [CrossRef] [PubMed]
  79. Hagiya, Y.; Endo, Y.; Yonemura, Y.; Takahashi, K.; Ishizuka, M.; Abe, F.; Tanaka, T.; Okura, I.; Nakajima, M.; Ishikawa, T.; et al. Pivotal roles of peptide transporter PEPT1 and ATP-binding cassette (ABC) transporter ABCG2 in 5-aminolevulinic acid (ALA)-based photocytotoxicity of gastric cancer cells in vitro. Photodiagnosis Photodyn. Ther. 2012, 9, 204–214. [Google Scholar] [CrossRef] [PubMed]
  80. Takahashi, H.; Nakajima, S.; Sakata, I.; Ishida-Yamamoto, A.; Iizuka, H. Photodynamic therapy using a novel photosensitizer, ATX-S10(Na): Comparative effect with 5-aminolevulinic acid on squamous cell carcinoma cell line, SCC15, ultraviolet B-induced skin tumor, and phorbol ester-induced hyperproliferative skin. Arch. Dermatol. Res. 2005, 296, 496–502. [Google Scholar] [CrossRef] [PubMed]
  81. Yang, D.F.; Chen, J.H.; Chiang, C.P.; Huang, Z.; Lee, J.W.; Liu, C.J.; Chang, J.L.; Hsu, Y.C. Improve efficacy of topical ALA-PDT by calcipotriol through up-regulation of coproporphyrinogen oxidase. Photodiagnosis Photodyn. Ther. 2014, 11, 331–341. [Google Scholar] [CrossRef]
  82. Yang, D.F.; Lee, J.W.; Chen, H.M.; Huang, Z.; Hsu, Y.C. Methotrexate enhances 5-aminolevulinic acid-mediated photodynamic therapy-induced killing of human SCC4 cells by upregulation of coproporphyrinogen oxidase. J. Formos. Med. Assoc. 2014, 113, 88–93. [Google Scholar] [CrossRef] [Green Version]
  83. JalalKamali, M.; Nematollahi-Mahani, S.N.; Shojaei, M.; Shamsoddini, A.; Arabpour, N. Effect of light polarization on the efficiency of photodynamic therapy of basal cell carcinomas: An in vitro cellular study. Lasers Med. Sci. 2018, 33, 305–313. [Google Scholar] [CrossRef] [PubMed]
  84. Wei, X.Q.; Ma, H.Q.; Liu, A.H.; Zhang, Y.Z. Synergistic anticancer activity of 5-aminolevulinic acid photodynamic therapy in combination with low-dose cisplatin on Hela cells. Asian Pac. J. Cancer Prev. 2013, 14, 3023–3028. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Zhou, X.; Wang, Y.; Si, J.; Zhou, R.; Gan, L.; Di, C.; Xie, Y.; Zhang, H. Laser controlled singlet oxygen generation in mitochondria to promote mitochondrial DNA replication in vitro. Sci. Rep. 2015, 5, 16925. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. He, G.F.; Bian, M.L.; Zhao, Y.W.; Xiang, Q.; Li, H.Y.; Xiao, C. Apoptosis-inducing effect of 5-aminolevulinic acid-mediated photodynamic therapy (5-ALA-PDT) on cervical cancer cell lines. Chin. J. Cancer 2008, 27, 195–200. [Google Scholar] [PubMed]
  87. McCarron, P.A.; Donnelly, R.F.; Gilmore, B.F.; Woolfson, A.D.; McClelland, R.; Zawislak, A.; Price, J.H. Phototoxicity of 5-aminolevulinic acid in the HeLa cell line as an indicative measure of photodynamic effect after topical administration to gynecological lesions of intraepithelial form. Pharm. Res. 2004, 21, 1871–1879. [Google Scholar] [CrossRef] [PubMed]
  88. Xie, J.; Wang, S.; Li, Z.; Ao, C.; Wang, J.; Wang, L.; Peng, X.; Zeng, K. 5-aminolevulinic acid photodynamic therapy reduces HPV viral load via autophagy and apoptosis by modulating Ras/Raf/MEK/ERK and PI3K/AKT pathways in HeLa cells. J. Photochem. Photobiol. B 2019, 194, 46–55. [Google Scholar] [CrossRef]
  89. He, G.F.; Bian, M.L.; Zhao, Y.W.; Xiang, Q.; Li, H.Y.; Xiao, C. A study on the mechanism of 5-aminolevulinic acid photodynamic therapy in vitro and in vivo in cervical cancer. Oncol. Rep. 2009, 21, 861–868. [Google Scholar] [CrossRef] [Green Version]
  90. Layer, P.G.; Robitzki, A.; Rothermel, A.; Willbold, E. Of layers and spheres: The reaggregate approach in tissue engineering. Trends Neurosci. 2002, 25, 131–134. [Google Scholar] [CrossRef]
  91. Jensen, C.; Teng, Y. Is It Time to Start Transitioning From 2D to 3D Cell Culture? Front. Mol. Biosci. 2020, 7, 33. [Google Scholar] [CrossRef] [Green Version]
  92. Knight, E.; Przyborski, S. Advances in 3D cell culture technologies enabling tissue-like structures to be created in vitro. J. Anat. 2015, 227, 746–756. [Google Scholar] [CrossRef] [Green Version]
  93. Edmondson, R.; Broglie, J.J.; Adcock, A.F.; Yang, L. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay. Drug. Dev. Technol. 2014, 12, 207–218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Wright, K.E.; MacRobert, A.J.; Phillips, J.B. Inhibition of specific cellular antioxidant pathways increases the sensitivity of neurons to meta-tetrahydroxyphenyl chlorin-mediated photodynamic therapy in a 3D co-culture model. Photochem. Photobiol. 2012, 88, 1539–1545. [Google Scholar] [CrossRef] [PubMed]
  95. Orlandi, V.T.; Martegani, E.; Bolognese, F. Catalase A is involved in the response to photooxidative stress in Pseudomonas aeruginosa. Photodiagnosis Photodyn. Ther. 2018, 22, 233–240. [Google Scholar] [CrossRef] [PubMed]
  96. Girotti, A.W.; Fahey, J.M.; Korytowski, W. Nitric oxide-elicited resistance to anti-glioblastoma photodynamic therapy. Cancer. Drug. Resist. 2020, 3, 401–414. [Google Scholar] [CrossRef] [PubMed]
  97. Theodossiou, T.A.; Olsen, C.E.; Jonsson, M.; Kubin, A.; Hothersall, J.S.; Berg, K. The diverse roles of glutathione-associated cell resistance against hypericin photodynamic therapy. Redox. Biol. 2017, 12, 191–197. [Google Scholar] [CrossRef] [PubMed]
  98. Yokoyama, Y.; Shigeto, T.; Miura, R.; Kobayashi, A.; Mizunuma, M.; Yamauchi, A.; Futagami, M.; Mizunuma, H. Differences in the sensitivity of ovarian cancer to photodynamic therapy and the mechanisms for those differences. Oncol. Lett. 2017, 13, 4933–4938. [Google Scholar] [CrossRef] [Green Version]
  99. Takahashi, T.; Misawa, S.; Suzuki, S.; Saeki, N.; Shinoda, Y.; Tsuneoka, Y.; Akimoto, J.; Fujiwara, Y. Possible mechanism of heme oxygenase-1 expression in rat malignant meningioma KMY-J cells subjected to talaporfin sodium-mediated photodynamic therapy. Photodiagnosis Photodyn. Ther. 2020, 32, 102009. [Google Scholar] [CrossRef] [PubMed]
  100. Franchi, L.P.; de Freitas Lima, J.E.B.; Piva, H.L.; Tedesco, A.C. The redox function of apurinic/apyrimidinic endonuclease 1 as key modulator in photodynamic therapy. J. Photochem. Photobiol. B 2020, 211, 111992. [Google Scholar] [CrossRef]
  101. Mikesova, L.; Mikes, J.; Koval, J.; Gyuraszova, K.; Culka, L.; Vargova, J.; Valekova, B.; Fedorocko, P. Conjunction of glutathione level, NAD(P)H/FAD redox status and hypericin content as a potential factor affecting colon cancer cell resistance to photodynamic therapy with hypericin. Photodiagnosis Photodyn. Ther. 2013, 10, 470–483. [Google Scholar] [CrossRef] [PubMed]
  102. Bunke, A.; Zerbe, O.; Schmid, H.; Burmeister, G.; Merkle, H.P.; Gander, B. Degradation mechanism and stability of 5-aminolevulinic acid. J. Pharm. Sci. 2000, 89, 1335–1341. [Google Scholar] [CrossRef]
  103. Ma, Y.; Qu, S.; Xu, L.; Lu, H.; Li, B. An in vitro study of the effect of 5-ALA-mediated photodynamic therapy on oral squamous cell carcinoma. BMC Oral Health 2020, 20, 258. [Google Scholar] [CrossRef] [PubMed]
  104. Liu, B.; Farrell, T.J.; Patterson, M.S. Comparison of photodynamic therapy with different excitation wavelengths using a dynamic model of aminolevulinic acid-photodynamic therapy of human skin. J. Biomed. Opt. 2012, 17, 088001. [Google Scholar] [CrossRef] [Green Version]
  105. Helander, L.; Krokan, H.E.; Johnsson, A.; Gederaas, O.A.; Plaetzer, K. Red versus blue light illumination in hexyl 5-aminolevulinate photodynamic therapy: The influence of light color and irradiance on the treatment outcome in vitro. J. Biomed. Opt. 2014, 19, 088002. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Di Venosa, G.; Vallecorsa, P.; Giuntini, F.; Mamone, L.; Batlle, A.; Vanzuli, S.; Juarranz, A.; MacRobert, A.J.; Eggleston, I.M.; Casas, A. The use of dipeptide derivatives of 5-aminolaevulinic acid promotes their entry to tumor cells and improves tumor selectivity of photodynamic therapy. Mol. Cancer Ther. 2015, 14, 440–451. [Google Scholar] [CrossRef] [Green Version]
  107. Perotti, C.; Fukuda, H.; DiVenosa, G.; MacRobert, A.J.; Batlle, A.; Casas, A. Porphyrin synthesis from ALA derivatives for photodynamic therapy. In vitro and in vivo studies. Br. J. Cancer 2004, 90, 1660–1665. [Google Scholar] [CrossRef] [Green Version]
  108. Yamamoto, J.; Yamamoto, S.; Hirano, T.; Li, S.; Koide, M.; Kohno, E.; Okada, M.; Inenaga, C.; Tokuyama, T.; Yokota, N.; et al. Monitoring of singlet oxygen is useful for predicting the photodynamic effects in the treatment for experimental glioma. Clin. Cancer Res. 2006, 12, 7132–7139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Angell-Petersen, E.; Spetalen, S.; Madsen, S.J.; Sun, C.H.; Peng, Q.; Carper, S.W.; Sioud, M.; Hirschberg, H. Influence of light fluence rate on the effects of photodynamic therapy in an orthotopic rat glioma model. J. Neurosurg. 2006, 104, 109–117. [Google Scholar] [CrossRef]
  110. Guney Eskiler, G.; Deveci Ozkan, A.; Sozen Kucukkara, E.; Kamanli, A.F.; Gunoglu, B.; Yildiz, M.Z. Optimization of 5-aminolevulinic acid-based photodynamic therapy protocol for breast cancer cells. Photodiagnosis Photodyn. Ther. 2020, 31, 101854. [Google Scholar] [CrossRef] [PubMed]
  111. Levine, E.M.; Becker, Y.; Boone, C.W.; Eagle, H. Contact Inhibition, Macromolecular Synthesis, and Polyribosomes in Cultured Human Diploid Fibroblasts. Proc. Natl. Acad. Sci. USA 1965, 53, 350–356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Fujishiro, T.; Nonoguchi, N.; Pavliukov, M.; Ohmura, N.; Kawabata, S.; Park, Y.; Kajimoto, Y.; Ishikawa, T.; Nakano, I.; Kuroiwa, T. 5-Aminolevulinic acid-mediated photodynamic therapy can target human glioma stem-like cells refractory to antineoplastic agents. Photodiagnosis Photodyn. Ther. 2018, 24, 58–68. [Google Scholar] [CrossRef] [PubMed]
  113. Tsai, J.C.; Hsiao, Y.Y.; Teng, L.J.; Chen, C.T.; Kao, M.C. Comparative study on the ALA photodynamic effects of human glioma and meningioma cells. Lasers Surg. Med. 1999, 24, 296–305. [Google Scholar] [CrossRef]
  114. Iinuma, S.; Farshi, S.S.; Ortel, B.; Hasan, T. A mechanistic study of cellular photodestruction with 5-aminolaevulinic acid-induced porphyrin. Br. J. Cancer 1994, 70, 21–28. [Google Scholar] [CrossRef] [PubMed]
Pharmaceuticals 14 00229 g001 550
Figure 1. Effectiveness of 5-ALA PDT in cells of different cancer classifications. GSC: glioblastoma stem cell, SCC: squamous cell carcinoma. There were no statistical significances (one-way analysis of variance (ANOVA) with the post hoc Tukey–Kramer test). Adenocarcinoma (n = 16) and glioblastoma (n = 10) were statistically assessed using the Wilcoxon rank-sum test but showed no significant differences.
Figure 1. Effectiveness of 5-ALA PDT in cells of different cancer classifications. GSC: glioblastoma stem cell, SCC: squamous cell carcinoma. There were no statistical significances (one-way analysis of variance (ANOVA) with the post hoc Tukey–Kramer test). Adenocarcinoma (n = 16) and glioblastoma (n = 10) were statistically assessed using the Wilcoxon rank-sum test but showed no significant differences.
Pharmaceuticals 14 00229 g001
Pharmaceuticals 14 00229 g002 550
Figure 2. Effectiveness of 5-ALA PDT on cells of different cancer origins. The stomach was identified as the organ most affected by 5-ALA PDT (one-way analysis of variance (ANOVA) with the post hoc Tukey–Kramer test). * p < 0.05 and ** p < 0.01 compared with the stomach. The brain (n = 18) and ovary (n = 7) were statistically assessed using the Wilcoxon rank-sum test but showed no significant differences.
Figure 2. Effectiveness of 5-ALA PDT on cells of different cancer origins. The stomach was identified as the organ most affected by 5-ALA PDT (one-way analysis of variance (ANOVA) with the post hoc Tukey–Kramer test). * p < 0.05 and ** p < 0.01 compared with the stomach. The brain (n = 18) and ovary (n = 7) were statistically assessed using the Wilcoxon rank-sum test but showed no significant differences.
Pharmaceuticals 14 00229 g002
Pharmaceuticals 14 00229 sch001 550
Scheme 1. Recommended experimental protocol for 5-ALA PDT. This protocol can be used as a standard protocol for in vitro 5-ALA PDT experiments. The duration of incubation (4 h may be a standard) can be changed if incubation time-dependency is investigated (*). Irradiance is particularly difficult to adjust because the light source is different in each lab, but the recommended irradiance is around 1 to 100 mW/cm2. Note that the experimental procedure indicated inside the gray box should be performed in the dark as much as possible because undesirable irradiation from the fluorescent lights of laminar flow cabinets and/or experimental rooms can increase ROS production and subsequent cell death. PBS: phosphate-buffered saline.
Scheme 1. Recommended experimental protocol for 5-ALA PDT. This protocol can be used as a standard protocol for in vitro 5-ALA PDT experiments. The duration of incubation (4 h may be a standard) can be changed if incubation time-dependency is investigated (*). Irradiance is particularly difficult to adjust because the light source is different in each lab, but the recommended irradiance is around 1 to 100 mW/cm2. Note that the experimental procedure indicated inside the gray box should be performed in the dark as much as possible because undesirable irradiation from the fluorescent lights of laminar flow cabinets and/or experimental rooms can increase ROS production and subsequent cell death. PBS: phosphate-buffered saline.
Pharmaceuticals 14 00229 sch001
Table
Table 1. In vitro 5-Aminolevulinic acid photodynamic therapy (5-ALA PDT) experiments for human cancer cell lines.
Table 1. In vitro 5-Aminolevulinic acid photodynamic therapy (5-ALA PDT) experiments for human cancer cell lines.
OrganClassificationName
[s]: Sphere		Effectiveness
(×10−4 cm2/(J·µM))		LC50 (μM)Duration of
Incubation (h)		Irradiation
Wavelength
(nm)		Fluence
(J/cm2)		Duration between
Irradiation and
Viability Assay (h)		Ref.
BladderCarcinomaHCV-290.2597463510024[32]
CarcinomaJ821.159746351524[32]
CarcinomaJ8212.05973590–7001.448[33]
CarcinomaRT11241.95973590–7000.448[33]
CarcinomaRT42.229846351524[32]
CarcinomaRT441.95973590–7000.448[33]
CarcinomaRT4 [s]20.95973400–7000.824[34]
BoneChordomaU-CH23.0181663518.7524[35]
OsteosarcomaHOSM-12.52006580–7402024[36]
OsteosarcomaHOSM-20.5100012600–16002024[37]
BrainAT/RTBT-161.137046352512[38]
GlioblastomaA1723.3100024635324[39]
GlioblastomaACBT [s]0.659746353024[40]
GlioblastomaU251MG3.310000.5All (white)320-24[41]
GlioblastomaU251MG5.0100046272O/N[42]
GlioblastomaU3733.7144463518.824[43]
GlioblastomaU3731.2650463512.7524[44]
GlioblastomaU3733.23154635 ± 201024[45]
GlioblastomaU373MG3.550026355.748[46]
GlioblastomaU373MG7.1100046271.4O/N[47]
GlioblastomaU373MG5.1100046351.9548[48]
GlioblastomaU373vIII0.71100463512.7524[44]
GlioblastomaU373vIII2.54074635 ± 201024[45]
GlioblastomaU871.5510463512.7524[44]
GlioblastomaU871.19314635 ± 201024[45]
GlioblastomaU87MG2.510000.5All (white)420–24[41]
GlioblastomaU87MG2.410006634 ± 74.148[31]
GlioblastomaU87MG4.2100046272.4O/N[47]
GlioblastomaU87MG3.3100046273O/N[42]
GlioblastomaU87vIII0.32800463512.7524[44]
GlioblastomaU87vIII0.911614635 ± 201024[45]
GSCBT273 [s]4.4122463518.824[43]
GSCBT275 [s]10.749.5463518.824[43]
GSCBT379 [s]8.860.3463518.824[43]
GSCGS3 [s]4.3124463518.824[43]
GSCGS5 [s]22.323.9463518.824[43]
Glioma stem cellGS22.6298463512.7524[44]
Glioma stem cellGS27.71304635 ± 201024[45]
Glioma stem cellGSC30 [s]10.8934635 ± 201024[45]
MedulloblastomaD283 Med5.350026353.848[46]
MedulloblastomaDaoy1.723946352512[38]
MeningiomaKT21-MG11.24482463518.751.5[49]
NeuroblastomaSK-N-SH1.410008500–7.248[50]
PNETPFSK-11.723946352512[38]
BreastAdenocarcinomaMDA-MB-2315.010000.5633 ± 6220[51]
AdenocarcinomaMDA-MB-2314.310006634 ± 72.348[31]
CarcinomaHB4a-Ras166.710003400-7000.0619[52]
CarcinomaT47D5.050024624 ± 5424[53]
CarcinomaT47D16.7100046350.648[48]
ColonAdenocarcinomaCaco-29.95973590–7001.748[54]
AdenocarcinomaHT-292.510003635424[55]
AdenocarcinomaHT-294.35973590–7003.948[54]
AdenocarcinomaSW4800.115004600–7205024[56]
AdenocarcinomaSW4800.115004600–7205324[57]
AdenocarcinomaSW4804.95973590–7003.448[54]
AdenocarcinomaSW6200.415004600–7201824[56]
AdenocarcinomaSW6200.410004600–7202424[57]
EsophagusSCCEca-1091.01000246301024[58]
SCCEca-1090.1750663010024[59]
GingivaSCCCa9-2220.8100036330.4824[60]
HypopharynxSCCFADU8.91000246351.1224[39]
KidneyCarcinomaA4981.210006634 ± 78.248[31]
LarynxSCCAMC-HN37.023924632624[61]
LiverCarcinomaHepG210.0100028600–80012[62]
CarcinomaHepG22.218536322524[63]
LungAdenocarcinomaLC-T1.050009600–7002.10[64]
CarcinomaH12995.01000463322.3[65]
CarcinomaQU-DB0.850009600–7002.50[64]
LymphLymphomaHuT7841.959.72630424[66]
LymphomaRamos (RA1)16.859.726301024[66]
NasopharynxCarcinomaHNE-13.032846301024[67]
CarcinomaKJ-13.6100036332.824[60]
Oral CavityDysplasiaDOK1.281046351024[68]
OvaryAdenocarcinomaES21.1882463110.424[69]
AdenocarcinomaKOC7C1.1857463110.424[69]
AdenocarcinomaOV27741.310004635848[48]
AdenocarcinomaOVMANA9.997463110.424[69]
AdenocarcinomaOVTOKO3.9244463110.424[69]
AdenocarcinomaRMG117.156463110.424[69]
AdenocarcinomaRMG217.156463110.424[69]
AdenocarcinomaTOV21G2.9330463110.424[69]
ProstateAdenocarcinomaLNCaP11.22984631324[70]
SkinMelanomaA3752.050046361024[71]
MelanomaA3750.63584420–14004524[72]
MelanomaLOX0.034000463510020[73]
SCCA4310.660003635 ± 930[74]
SCCA43117.0393206301.524[30]
SCCA43112.510024632.8824[75]
SCCA4310.1200046354024[76]
SCCA4311131.91.7748630 ± 15548[77]
SCCHSC-51.02002545–700503[78]
SCCSCC-130.160001635 ± 912.210[74]
StomachAdenocarcinomaKKLS13.270046301.0824[79]
AdenocarcinomaMKN2823.140046301.0824[79]
AdenocarcinomaMKN45185.25046301.0824[79]
TongueSCCCAL-271.662046351024[68]
SCCSCC-1511.259.712630156[80]
SCCSCC-45.318746401024[81]
SCCSCC-42.737546401024[82]
UterusAdenocarcinomaBCC16.75004.5532 ± 201.220[83]
AdenocarcinomaHeLa4.05004635524[84]
AdenocarcinomaHeLa100.020086300.524[85]
AdenocarcinomaHeLa98.010.26630103[86]
AdenocarcinomaHeLa0.3300463510020[87]
AdenocarcinomaHeLa16.71000246350.624[88]
AdenocarcinomaKB1.32006580–7404024[36]
SCCC-33A588.21.76630103[86]
SCCC-4 I12.977.76630103[86]
SCCCa Ski28.435.26630103[86]
SCCHT-33.03326630103[86]
SCCMe-1801373.60.7286630103[86]
SCCMe-180660.10.5054632.8304[89]
SCCSiHa3.03326630103[86]
AT/RT: atypical teratoid/rhabdoid tumor, GSC: glioblastoma stem cell, SCC: squamous cell carcinoma, PNET: primitive neuroectodermal tumor, O/N: overnight; LC50, median lethal concentration.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Shinoda, Y.; Kato, D.; Ando, R.; Endo, H.; Takahashi, T.; Tsuneoka, Y.; Fujiwara, Y. Systematic Review and Meta-Analysis of In Vitro Anti-Human Cancer Experiments Investigating the Use of 5-Aminolevulinic Acid (5-ALA) for Photodynamic Therapy. Pharmaceuticals 2021, 14, 229. https://doi.org/10.3390/ph14030229

AMA Style

Shinoda Y, Kato D, Ando R, Endo H, Takahashi T, Tsuneoka Y, Fujiwara Y. Systematic Review and Meta-Analysis of In Vitro Anti-Human Cancer Experiments Investigating the Use of 5-Aminolevulinic Acid (5-ALA) for Photodynamic Therapy. Pharmaceuticals. 2021; 14(3):229. https://doi.org/10.3390/ph14030229

Chicago/Turabian Style

Shinoda, Yo, Daitetsu Kato, Ryosuke Ando, Hikaru Endo, Tsutomu Takahashi, Yayoi Tsuneoka, and Yasuyuki Fujiwara. 2021. "Systematic Review and Meta-Analysis of In Vitro Anti-Human Cancer Experiments Investigating the Use of 5-Aminolevulinic Acid (5-ALA) for Photodynamic Therapy" Pharmaceuticals 14, no. 3: 229. https://doi.org/10.3390/ph14030229

APA Style

Shinoda, Y., Kato, D., Ando, R., Endo, H., Takahashi, T., Tsuneoka, Y., & Fujiwara, Y. (2021). Systematic Review and Meta-Analysis of In Vitro Anti-Human Cancer Experiments Investigating the Use of 5-Aminolevulinic Acid (5-ALA) for Photodynamic Therapy. Pharmaceuticals, 14(3), 229. https://doi.org/10.3390/ph14030229

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop