Pharmaceutics

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21 pages, 9972 KiB

Open AccessArticle

Effects of Lactate Transport Inhibition by AZD3965 in Muscle-Invasive Urothelial Bladder Cancer

by Ana Silva, Ana Félix, Mónica Cerqueira, Céline S. Gonçalves, Belém Sampaio-Marques, Adhemar Longatto-Filho, Fátima Baltazar and Julieta Afonso

Pharmaceutics 2023, 15(12), 2688; https://doi.org/10.3390/pharmaceutics15122688 - 28 Nov 2023

Cited by 1 | Viewed by 1714

Abstract

The Warburg Effect is characterized by high rates of glucose uptake and lactate production. Monocarboxylate transporters (MCTs) are crucial to avoid cellular acidosis by internal lactate accumulation, being largely overexpressed by cancer cells and associated with cancer aggressiveness. The MCT1-specific inhibitor AZD3965 has [...] Read more.

The Warburg Effect is characterized by high rates of glucose uptake and lactate production. Monocarboxylate transporters (MCTs) are crucial to avoid cellular acidosis by internal lactate accumulation, being largely overexpressed by cancer cells and associated with cancer aggressiveness. The MCT1-specific inhibitor AZD3965 has shown encouraging results in different cancer models. However, it has not been tested in urothelial bladder cancer (UBC), a neoplasm where rates of recurrence, progression and platinum-based resistance are generally elevated. We used two muscle-invasive UBC cell lines to study AZD3965 activity regarding lactate production, UBC cells’ viability and proliferation, cell cycle profile, and migration and invasion properties. An “in vivo” assay with the chick chorioallantoic membrane model was additionally performed, as well as the combination of the compound with cisplatin. AZD3965 demonstrated anticancer activity upon low levels of MCT4, while a general lack of sensitivity was observed under MCT4 high expression. Cell viability, proliferation and migration were reduced, cell cycle was arrested, and tumor growth “in vivo” was inhibited. The compound sensitized these MCT4-low-expressing cells to cisplatin. Thus, AZD3965 seems to display anticancer properties in UBC under a low MCT4-expression setting, but additional studies are necessary to confirm AZD3965 activity in this cancer model. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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18 pages, 6963 KiB

Open AccessEditor’s ChoiceArticle

RNAi-Mediated Knockdown of Cottontail Rabbit Papillomavirus Oncogenes Using Low-Toxicity Lipopolyplexes as a Paradigm to Treat Papillomavirus-Associated Cancers

by Uzma Ali, Michael Bette, Ghazala Ambreen, Shashank R. Pinnapireddy, Imran Tariq, André Marquardt, Boris A. Stuck, Udo Bakowsky and Robert Mandic

Pharmaceutics 2023, 15(10), 2379; https://doi.org/10.3390/pharmaceutics15102379 - 25 Sep 2023

Viewed by 1716

Abstract

The cottontail rabbit papillomavirus (CRPV)-associated VX2 carcinoma of the New Zealand White rabbit serves as a model system for human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCCs). The aim of this study was to evaluate the tumor-inhibiting effect of RNAi-mediated knockdown [...] Read more.

The cottontail rabbit papillomavirus (CRPV)-associated VX2 carcinoma of the New Zealand White rabbit serves as a model system for human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCCs). The aim of this study was to evaluate the tumor-inhibiting effect of RNAi-mediated knockdown of the CRPV oncogenes, E6 and E7, using siRNA-loaded lipopolyplexes (LPPs). VX2-carcinoma-derived cells were cultured for up to 150 passages. In addition, CRPV E6 and E7 oncogenes were transiently expressed in COS-7 cells. Efficiency and safety of LPPs were evaluated in both VX2 cells and the COS-7 cell line. Both of these in vitro CRPV systems were validated and characterized by fluorescence microscopy, Western blot, and RT-qPCR. Efficient knockdown of CRPV E6 and E7 was achieved in VX2 cells and COS-7 cells pretransfected with CRPV E6 and E7 expression vectors. Knockdown of CRPV oncogenes in VX2 cells resulted in reduced viability, migration, and proliferation and led to a G0/G1 block in the cell cycle. CRPV E6 and E7 siRNA-loaded LPPs could represent promising therapeutic agents serving as a paradigm for the treatment of papillomavirus-positive cancers and could be of value for the treatment of CRPV-associated diseases in the rabbit such as papillomas and cancers of the skin. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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15 pages, 4248 KiB

Open AccessArticle

Improving Overall Survival and Quality of Life in Patients with Prostate Cancer and Neuroendocrine Tumors Using ¹⁷⁷Lu-iPSMA and ¹⁷⁷Lu-DOTATOC: Experience after 905 Treatment Doses

by Myrna Luna-Gutiérrez, Rodrigo Hernández-Ramírez, Airam Soto-Abundiz, Osvaldo García-Pérez, Alejandra Ancira-Cortez, Sergio López-Buenrostro, Brenda Gibbens-Bandala, Irma Soldevilla-Gallardo, Nancy Lara-Almazán, Melissa Rojas-Pérez, Blanca Ocampo-García, Erika Azorín-Vega, Clara Santos-Cuevas and Guillermina Ferro-Flores

Pharmaceutics 2023, 15(7), 1988; https://doi.org/10.3390/pharmaceutics15071988 - 20 Jul 2023

Cited by 2 | Viewed by 2408

Abstract

¹⁷⁷Lu-iPSMA is a novel radioligand developed at ININ-Mexico with a high affinity for the PSMA protein heavily expressed in cancer cells of approximately 95% of patients with metastatic castration-resistant prostate cancer (mCRPC). ¹⁷⁷Lu-DOTATOC is a patent-free radioligand, molecularly recognized by somatostatin [...] Read more.

¹⁷⁷Lu-iPSMA is a novel radioligand developed at ININ-Mexico with a high affinity for the PSMA protein heavily expressed in cancer cells of approximately 95% of patients with metastatic castration-resistant prostate cancer (mCRPC). ¹⁷⁷Lu-DOTATOC is a patent-free radioligand, molecularly recognized by somatostatin receptors (SSTR-2) overexpressed in cancer cells of about 80% of patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET). This translational research aimed to determine the efficacy and safety of ¹⁷⁷Lu-iPSMA and ¹⁷⁷Lu-DOTATOC developed as GMP pharmaceutical formulations for treating progressive and advanced mCRPC and NET. One hundred and forty-five patients with mCRPC and one hundred and eighty-seven subjects with progressive NET (83% GEP-NET and 17% other NET), treated with ¹⁷⁷Lu-iPSMA and ¹⁷⁷Lu-DOTATOC, respectively, were evaluated. Patients received a mean dose of 7.4 GBq per administration of ¹⁷⁷Lu-iPSMA (range 1–5 administrations; 394 treatment doses) or ¹⁷⁷Lu-DOTATOC (range 2–8 administrations; 511 treatment doses) at intervals of 1.5–2.5 months. Efficacy was assessed by SPECT/CT or PET/CT. Results were stratified by primary tumor origin and number of doses administered. Patients with mCRPC showed overall survival (OS) of 21.7 months with decreased radiotracer tumor uptake (SUV) and PSA level in 80% and 73% of patients, respectively. In addition, a significant reduction in pain (numerical scale from 10–7 to 3–1) was observed in 88% of patients with bone metastases between one and two weeks after the second injection. In the GEP-NET population, the median progression-free survival was 34.7 months, with an OS of >44.2 months. The treatments were well tolerated. Only ten patients experienced grade ≥ 3 myelosuppression (3% of all patients). The observed safety profiles and favorable therapeutic responses demonstrated the potential of ¹⁷⁷Lu-iPSMA and ¹⁷⁷Lu-DOTATOC to improve overall survival and quality of life in patients with progressive and advanced mCRPC and NET. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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22 pages, 6315 KiB

Open AccessEditor’s ChoiceArticle

Multifunctional Polymeric Biodegradable and Biocompatible Coatings Based on Silver Nanoparticles: A Comparative In Vitro Study on Their Cytotoxicity towards Cancer and Normal Cell Lines of Cytostatic Drugs versus Essential-Oil-Loaded Nanoparticles and on Their Antimicrobial and Antibiofilm Activities

by Rebecca Alexandra Puiu, Alexandra Cătălina Bîrcă, Valentina Grumezescu, Liviu Duta, Ovidiu Cristian Oprea, Alina Maria Holban, Ariana Hudiță, Bianca Gălățeanu, Paul Cătălin Balaure, Alexandru Mihai Grumezescu and Ecaterina Andronescu

Pharmaceutics 2023, 15(7), 1882; https://doi.org/10.3390/pharmaceutics15071882 - 4 Jul 2023

Cited by 6 | Viewed by 1840

Abstract

We report on a comparative in vitro study of selective cytotoxicity against MCF7 tumor cells and normal VERO cells tested on silver-based nanocoatings synthesized by the matrix-assisted pulsed laser evaporation (MAPLE) technique. Silver nanoparticles (AgNPs) were loaded with five representative cytostatic drugs (i.e., [...] Read more.

We report on a comparative in vitro study of selective cytotoxicity against MCF7 tumor cells and normal VERO cells tested on silver-based nanocoatings synthesized by the matrix-assisted pulsed laser evaporation (MAPLE) technique. Silver nanoparticles (AgNPs) were loaded with five representative cytostatic drugs (i.e., doxorubicin, fludarabine, paclitaxel, gemcitabine, and carboplatin) and with five essential oils (EOs) (i.e., oregano, rosemary, ginger, basil, and thyme). The as-obtained coatings were characterized by X-ray diffraction, thermogravimetry coupled with differential scanning calorimetry, Fourier-transform IR spectroscopy, IR mapping, and scanning electron microscopy. A screening of the impact of the prepared nanocoatings on the MCF7 tumor and normal VERO cell lines was achieved by means of cell viability MTT and cytotoxicity LDH assays. While all nanocoatings loaded with antitumor drugs exhibited powerful cytotoxic activity against both the tumor and the normal cells, those embedded with AgNPs loaded with rosemary and thyme EOs showed remarkable and statistically significant selective cytotoxicity against the tested cancercells. The EO-loaded nanocoatings were tested for antimicrobial and antibiofilm activity against Staphylococcus aureus, Escherichia coli, and Candida albicans. For all studied pathogens, the cell viability, assessed by counting the colony-forming units after 2 and 24 h, was significantly decreased by all EO-based nanocoatings, while the best antibiofilm activity was evidenced by the nanocoatings containing ginger and thyme EOs. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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16 pages, 5151 KiB

Open AccessArticle

Development of pH-Responsive Hyaluronic Acid-Conjugated Cyclodextrin Nanoparticles for Chemo-/CO-Gas Dual Therapy

by Eunsol Lee and Eun Seong Lee

Pharmaceutics 2023, 15(7), 1818; https://doi.org/10.3390/pharmaceutics15071818 - 25 Jun 2023

Cited by 1 | Viewed by 1638

Abstract

In this study, we fabricated γ-cyclodextrin (γCD)-based nanoparticles (NPs) for dual antitumor therapy. First, γCD (the backbone biopolymer) was chemically conjugated with low-molecular-weight hyaluronic acid (HA; a tumoral CD44 receptor-targeting molecule) and 3-(diethylamino)propylamine (DEAP; a pH-responsive molecule), termed as γCD-(DEAP/HA). The obtained γCD-(DEAP/HA) [...] Read more.

In this study, we fabricated γ-cyclodextrin (γCD)-based nanoparticles (NPs) for dual antitumor therapy. First, γCD (the backbone biopolymer) was chemically conjugated with low-molecular-weight hyaluronic acid (HA; a tumoral CD44 receptor-targeting molecule) and 3-(diethylamino)propylamine (DEAP; a pH-responsive molecule), termed as γCD-(DEAP/HA). The obtained γCD-(DEAP/HA) self-assembled in aqueous solution, producing the γCD-(DEAP/HA) NPs. These NPs efficiently entrapped paclitaxel (PTX; an antitumor drug) and triiron dodecacarbonyl (FeCO; an endogenous cytotoxic gas molecule) via hydrophobic interactions between PTX and FeCO with the unprotonated DEAP molecules in γCD-(DEAP/HA) and a possible host–guest interaction in the γCD rings. The release of PTX and FeCO from the NPs resulted from particle destabilization at endosomal pH, probably owing to the protonation of DEAP in the NPs. In vitro studies using MCF-7 tumor cells demonstrated that these NPs were efficiently internalized by the cells expressing CD44 receptors and enhanced PTX/FeCO-mediated tumor cell apoptosis. Importantly, local light irradiation of FeCO stimulated the generation of cytotoxic CO, resulting in highly improved tumor cell death. We expect that these NPs have potential as dual-modal therapeutic candidates with enhanced antitumor activity in response to acidic pH and local light irradiation. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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32 pages, 13058 KiB

Open AccessArticle

New Ruthenium-Cyclopentadienyl Complexes Affect Colorectal Cancer Hallmarks Showing High Therapeutic Potential

by Ana Rita Brás, Pedro Fernandes, Tiago Moreira, Julia Morales-Sanfrutos, Eduard Sabidó, Alexandra M. M. Antunes, Andreia Valente and Ana Preto

Pharmaceutics 2023, 15(6), 1731; https://doi.org/10.3390/pharmaceutics15061731 - 14 Jun 2023

Cited by 2 | Viewed by 1758

Abstract

Colorectal cancer (CRC) is among the most deadly cancers worldwide. Current therapeutic strategies have low success rates and several side effects. This relevant clinical problem requires the discovery of new and more effective therapeutic alternatives. Ruthenium drugs have arisen as one of the [...] Read more.

Colorectal cancer (CRC) is among the most deadly cancers worldwide. Current therapeutic strategies have low success rates and several side effects. This relevant clinical problem requires the discovery of new and more effective therapeutic alternatives. Ruthenium drugs have arisen as one of the most promising metallodrugs, due to their high selectivity to cancer cells. In this work we studied, for the first time, the anticancer properties and mechanisms of action of four lead Ru-cyclopentadienyl compounds, namely PMC79, PMC78, LCR134 and LCR220, in two CRC-derived cell lines (SW480 and RKO). Biological assays were performed on these CRC cell lines to evaluate cellular distribution, colony formation, cell cycle, proliferation, apoptosis, and motility, as well as cytoskeleton and mitochondrial alterations. Our results show that all the compounds displayed high bioactivity and selectivity, as shown by low half-maximal inhibitory concentrations (IC₅₀) against CRC cells. We observed that all the Ru compounds have different intracellular distributions. In addition, they inhibit to a high extent the proliferation of CRC cells by decreasing clonogenic ability and inducing cell cycle arrest. PMC79, LCR134, and LCR220 also induce apoptosis, increase the levels of reactive oxygen species, lead to mitochondrial dysfunction, induce actin cytoskeleton alterations, and inhibit cellular motility. A proteomic study revealed that these compounds cause modifications in several cellular proteins associated with the phenotypic alterations observed. Overall, we demonstrate that Ru compounds, especially PMC79 and LCR220, display promising anticancer activity in CRC cells with a high potential to be used as new metallodrugs for CRC therapy. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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20 pages, 5288 KiB

Open AccessArticle

System Analysis Based on Lipid-Metabolism-Related Genes Identifies AGT as a Novel Therapy Target for Gastric Cancer with Neoadjuvant Chemotherapy

by Le Zhu, Ming Ma, Lumin Zhang, Shun Wang, Yu Guo, Xinxin Ling, Hanchao Lin, Nannan Lai, Shengli Lin, Ling Du and Qiongzhu Dong

Pharmaceutics 2023, 15(3), 810; https://doi.org/10.3390/pharmaceutics15030810 - 2 Mar 2023

Cited by 2 | Viewed by 2192

Abstract

Gastric cancer (GC) is one of the most common causes of cancer-related deaths worldwide, and chemotherapy is still a standard strategy for treating patients with advanced GC. Lipid metabolism has been reported to play an important role in the carcinogenesis and development of [...] Read more.

Gastric cancer (GC) is one of the most common causes of cancer-related deaths worldwide, and chemotherapy is still a standard strategy for treating patients with advanced GC. Lipid metabolism has been reported to play an important role in the carcinogenesis and development of GC. However, the potential values of lipid-metabolism-related genes (LMRGs) concerning prognostic value and the prediction of chemotherapy responsiveness in GC remains unclear. A total of 714 stomach adenocarcinoma patients were enrolled from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Using univariate Cox and LASSO regression analyses, we developed a risk signature based on LMRGs that can distinguish high-GC-risk patients from low-risk patients with significant differences in overall survival. We further validated this signature prognostic value using the GEO database. The R package “pRRophetic” was applied to calculate the sensitivity of each sample from high- and low-risk groups to chemotherapy drugs. The expression of two LMRGs, AGT and ENPP7, can predict the prognosis and response to chemotherapy in GC. Furthermore, AGT significantly promoted GC growth and migration, and the downregulation of AGT enhanced the chemotherapy response of GC both in vitro and in vivo. Mechanistically, AGT induced significant levels of epithelial–mesenchymal transition (EMT) through the PI3K/AKT pathway. The PI3K/AKT pathway agonist 740 Y-P can restore the EMT of GC cells impaired by AGT knockdown and treatment with 5-fluorouracil. Our findings suggest that AGT plays a key role in the development of GC, and targeting AGT may help to improve the chemotherapy response of GC patients. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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16 pages, 3569 KiB

Open AccessArticle

In Vitro Photodynamic Treatment Modality for A375 Melanoma Cell Line Using a Sulphonated Aluminum Phthalocyanine Chloride-Photosensitizer-Gold Nanoparticle Conjugate

by Bridgette Mkhobongo, Rahul Chandran and Heidi Abrahamse

Pharmaceutics 2022, 14(11), 2474; https://doi.org/10.3390/pharmaceutics14112474 - 16 Nov 2022

Cited by 11 | Viewed by 2272

Abstract

Metastatic melanoma cancer stem cells are subpopulations that have been identified and linked to tumor progression, immunoevasive behavior, drug resistance, and metastasis, leading to a poor prognosis. Photodynamic therapy (PDT) is an approach to eradicate cancer through a photochemical process which directly generates [...] Read more.

Metastatic melanoma cancer stem cells are subpopulations that have been identified and linked to tumor progression, immunoevasive behavior, drug resistance, and metastasis, leading to a poor prognosis. Photodynamic therapy (PDT) is an approach to eradicate cancer through a photochemical process which directly generates reactive oxygen species (ROS). This study investigated the impact of PDT using an aluminum phthalocyanine gold nanoparticle (AlPcS₄Cl-AuNP) conjugate for targeting melanoma stem cells. The isolated stem cells were irradiated at 673.2 nm with a radiant exposure of 5 J/cm². Post-irradiation signs of cell death were determined using microscopy and biochemical assays. A possible enhanced effect of ROS in inducing cell death could be seen when AlPcS₄Cl was conjugated to AuNPs. Nanoparticles as carriers promote the efficient cellular uptake of photosensitizers, enhancing organelle accumulation and the targeted therapy of cancerous cells. A biochemical assay revealed significant post-irradiation signs of cell death. The measurement of adenosine triphosphate (ATP) content revealed a decrease in cell proliferation. The study suggested an approach directed at expanding the knowledge on PDT to improve cancer treatment. Understanding the cell death mechanism through which ROS influence cancer stem cells (CSCs) is, therefore, useful for improving PDT efficiency and preventing tumor recurrence and metastasis. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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19 pages, 4881 KiB

Open AccessArticle

Photodynamic Therapy Efficacy of Novel Zinc Phthalocyanine Tetra Sodium 2-Mercaptoacetate Combined with Cannabidiol on Metastatic Melanoma

by Nkune Williams Nkune, Gauta Gold Matlou and Heidi Abrahamse

Pharmaceutics 2022, 14(11), 2418; https://doi.org/10.3390/pharmaceutics14112418 - 9 Nov 2022

Cited by 8 | Viewed by 1973

Abstract

This work reports for the first time on the synthesis, characterization, and photodynamic therapy effect of a novel water-soluble zinc (II) 2(3), 9(10), 16(17), 23(24)-tetrakis-(sodium 2-mercaptoacetate) phthalocyanine (ZnPcTS41), on metastatic melanoma cells (A375) combined with cannabidiol (CBD). The ZnPcTS41 structure was confirmed using [...] Read more.

This work reports for the first time on the synthesis, characterization, and photodynamic therapy effect of a novel water-soluble zinc (II) 2(3), 9(10), 16(17), 23(24)-tetrakis-(sodium 2-mercaptoacetate) phthalocyanine (ZnPcTS41), on metastatic melanoma cells (A375) combined with cannabidiol (CBD). The ZnPcTS41 structure was confirmed using FTIR, NMR, MS, and elemental analysis while the electronic absorption spectrum was studied using UV-VIS. The study reports further on the dose-dependent effects of ZnPcTS41 (1–8 µM) and CBD alone (0.3–1.1 µM) at 636 nm with 10 J/cm² on cellular morphology and viability. The IC₅₀ concentrations of ZnPcTS41 and CBD were found to be 5.3 µM and 0.63 µM, respectively. The cytotoxicity effects of the ZnPcTS41 enhanced with CBD on A375 cells were assessed using MTT cell viability assay, ATP cellular proliferation and inverted light microscopy. Cell death induction was also determined via Annexin V-FITC-PI. The combination of CBD- and ZnPcTS41-mediated PDT resulted in a significant reduction in cell viability (15%***) and an increase in the late apoptotic cell population (25%*). These findings suggest that enhancing PDT with anticancer agents such as CBD could possibly obliterate cancer cells and inhibit tumor recurrence. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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22 pages, 3422 KiB

Open AccessArticle

Microbiota-Derived Short-Chain Fatty Acids: New Road in Colorectal Cancer Therapy

by Sara Gomes, Fátima Baltazar, Elisabete Silva and Ana Preto

Pharmaceutics 2022, 14(11), 2359; https://doi.org/10.3390/pharmaceutics14112359 - 1 Nov 2022

Cited by 19 | Viewed by 2645

Abstract

The colon microbiota is an important player in colorectal cancer (CRC) development, which is responsible for most of the cancer-related deaths worldwide. During carcinogenesis, the colon microbiota composition changes from a normobiosis profile to dysbiosis, interfering with the production of short-chain fatty acids [...] Read more.

The colon microbiota is an important player in colorectal cancer (CRC) development, which is responsible for most of the cancer-related deaths worldwide. During carcinogenesis, the colon microbiota composition changes from a normobiosis profile to dysbiosis, interfering with the production of short-chain fatty acids (SCFAs). Each SCFA is known to play a role in several biological processes but, despite their reported individual effects, colon cells are exposed to these compounds simultaneously and the combined effect of SCFAs in colon cells is still unknown. Our aim was to explore the effects of SCFAs, alone or in combination, unveiling their biological impact on CRC cell phenotypes. We used a mathematical model for the prediction of the expected SCFA mixture effects and found that, when in mixture, SCFAs exhibit a concentration addition behavior. All SCFAs, alone or combined at the physiological proportions founded in the human colon, revealed to have a selective and anticancer effect by inhibiting colony formation and cell proliferation, increasing apoptosis, disturbing the energetic metabolism, inducing lysosomal membrane permeabilization, and decreasing cytosolic pH. We showed for the first time that SCFAs are specific towards colon cancer cells, showing promising therapeutic effects. These findings open a new road for the development of alternatives for CRC therapy based on the increase in SCFA levels through the modulation of the colon microbiota composition. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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Review

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34 pages, 1012 KiB

Open AccessReview

miRNA-Mediated Mechanisms in the Generation of Effective and Safe Oncolytic Viruses

by Mariia Toropko, Sergey Chuvpilo and Alexander Karabelsky

Pharmaceutics 2024, 16(8), 986; https://doi.org/10.3390/pharmaceutics16080986 - 25 Jul 2024

Viewed by 927

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by inhibiting the translation of target transcripts. The expression profiles of miRNAs vary in different tissues and change with the development of diseases, including cancer. This feature has begun to be used for [...] Read more.

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by inhibiting the translation of target transcripts. The expression profiles of miRNAs vary in different tissues and change with the development of diseases, including cancer. This feature has begun to be used for the modification of oncolytic viruses (OVs) in order to increase their selectivity and efficacy. OVs represent a relatively new class of anticancer drugs; they are designed to replicate in cancer tumors and destroy them. These can be natural viruses that can replicate within cancer tumor cells, or recombinant viruses created in laboratories. There are some concerns regarding OVs’ toxicity, due to their ability to partially replicate in healthy tissues. In addition, lytic and immunological responses upon OV therapy are not always sufficient, so various OV editing methods are used. This review discusses the latest results of preclinical and clinical studies of OVs, modifications of which are associated with the miRNA-mediated mechanism of gene silencing. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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20 pages, 4226 KiB

Open AccessEditor’s ChoiceReview

Natural Chalcones and Derivatives in Colon Cancer: Pre-Clinical Challenges and the Promise of Chalcone-Based Nanoparticles

by Soufyane Hba, Suzan Ghaddar, Hicham Wahnou, Aline Pinon, Riad El Kebbaj, Christelle Pouget, Vincent Sol, Bertrand Liagre, Mounia Oudghiri and Youness Limami

Pharmaceutics 2023, 15(12), 2718; https://doi.org/10.3390/pharmaceutics15122718 - 1 Dec 2023

Cited by 5 | Viewed by 2051

Abstract

Colon cancer poses a complex and substantial global health challenge, necessitating innovative therapeutic approaches. Chalcones, a versatile class of compounds with diverse pharmacological properties, have emerged as promising candidates for addressing colon cancer. Their ability to modulate pivotal signaling pathways in the development [...] Read more.

Colon cancer poses a complex and substantial global health challenge, necessitating innovative therapeutic approaches. Chalcones, a versatile class of compounds with diverse pharmacological properties, have emerged as promising candidates for addressing colon cancer. Their ability to modulate pivotal signaling pathways in the development and progression of colon cancer makes them invaluable as targeted therapeutics. Nevertheless, it is crucial to recognize that although chalcones exhibit promise, further pre-clinical studies are required to validate their efficacy and safety. The journey toward effective colon cancer treatment is multifaceted, involving considerations such as optimizing the sequencing of therapeutic agents, comprehending the resistance mechanisms, and exploring combination therapies incorporating chalcones. Furthermore, the integration of nanoparticle-based drug delivery systems presents a novel avenue for enhancing the effectiveness of chalcones in colon cancer treatment. This review delves into the mechanisms of action of natural chalcones and some derivatives. It highlights the challenges associated with their use in pre-clinical studies, while also underscoring the advantages of employing chalcone-based nanoparticles for the treatment of colon cancer. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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19 pages, 2681 KiB

Open AccessReview

Unleashing the Power of Synthetic Lethality: Augmenting Treatment Efficacy through Synergistic Integration with Chemotherapy Drugs

by Yajing Du, Lulu Luo, Xinru Xu, Xinbing Yang, Xueni Yang, Shizheng Xiong, Jiafeng Yu, Tingming Liang and Li Guo

Pharmaceutics 2023, 15(10), 2433; https://doi.org/10.3390/pharmaceutics15102433 - 8 Oct 2023

Cited by 3 | Viewed by 2337

Abstract

Cancer is the second leading cause of death in the world, and chemotherapy is one of the main methods of cancer treatment. However, the resistance of cancer cells to chemotherapeutic drugs has always been the main reason affecting the therapeutic effect. Synthetic lethality [...] Read more.

Cancer is the second leading cause of death in the world, and chemotherapy is one of the main methods of cancer treatment. However, the resistance of cancer cells to chemotherapeutic drugs has always been the main reason affecting the therapeutic effect. Synthetic lethality has emerged as a promising approach to augment the sensitivity of cancer cells to chemotherapy agents. Synthetic lethality (SL) refers to the specific cell death resulting from the simultaneous mutation of two non-lethal genes, which individually allow cell survival. This comprehensive review explores the classification of SL, screening methods, and research advancements in SL inhibitors, including Poly (ADP-ribose) polymerase (PARP) inhibitors, Ataxia telangiectasia and Rad3-related (ATR) inhibitors, WEE1 G2 checkpoint kinase (WEE1) inhibitors, and protein arginine methyltransferase 5 (PRMT5) inhibitors. Emphasizing their combined use with chemotherapy drugs, we aim to unveil more effective treatment strategies for cancer patients. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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21 pages, 4647 KiB

Open AccessReview

Smart Delivery Systems Responsive to Cathepsin B Activity for Cancer Treatment

by Vera S. Egorova, Ekaterina P. Kolesova, Manu Lopus, Neng Yan, Alessandro Parodi and Andrey A. Zamyatnin, Jr.

Pharmaceutics 2023, 15(7), 1848; https://doi.org/10.3390/pharmaceutics15071848 - 29 Jun 2023

Cited by 7 | Viewed by 3251

Abstract

Cathepsin B is a lysosomal cysteine protease, contributing to vital cellular homeostatic processes including protein turnover, macroautophagy of damaged organelles, antigen presentation, and in the extracellular space, it takes part in tissue remodeling, prohormone processing, and activation. However, aberrant overexpression of cathepsin B [...] Read more.

Cathepsin B is a lysosomal cysteine protease, contributing to vital cellular homeostatic processes including protein turnover, macroautophagy of damaged organelles, antigen presentation, and in the extracellular space, it takes part in tissue remodeling, prohormone processing, and activation. However, aberrant overexpression of cathepsin B and its enzymatic activity is associated with different pathological conditions, including cancer. Cathepsin B overexpression in tumor tissues makes this enzyme an important target for smart delivery systems, responsive to the activity of this enzyme. The generation of technologies which therapeutic effect is activated as a result of cathepsin B cleavage provides an opportunity for tumor-targeted therapy and controlled drug release. In this review, we summarized different technologies designed to improve current cancer treatments responsive to the activity of this enzyme that were shown to play a key role in disease progression and response to the treatment. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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18 pages, 1511 KiB

Open AccessReview

The Exploitation of Lysosomes in Cancer Therapy with Graphene-Based Nanomaterials

by Biljana Ristic, Mihajlo Bosnjak, Maja Misirkic Marjanovic, Danijela Stevanovic, Kristina Janjetovic and Ljubica Harhaji-Trajkovic

Pharmaceutics 2023, 15(7), 1846; https://doi.org/10.3390/pharmaceutics15071846 - 28 Jun 2023

Cited by 4 | Viewed by 1982

Abstract

Graphene-based nanomaterials (GNMs), including graphene, graphene oxide, reduced graphene oxide, and graphene quantum dots, may have direct anticancer activity or be used as nanocarriers for antitumor drugs. GNMs usually enter tumor cells by endocytosis and can accumulate in lysosomes. This accumulation prevents drugs [...] Read more.

Graphene-based nanomaterials (GNMs), including graphene, graphene oxide, reduced graphene oxide, and graphene quantum dots, may have direct anticancer activity or be used as nanocarriers for antitumor drugs. GNMs usually enter tumor cells by endocytosis and can accumulate in lysosomes. This accumulation prevents drugs bound to GNMs from reaching their targets, suppressing their anticancer effects. A number of chemical modifications are made to GNMs to facilitate the separation of anticancer drugs from GNMs at low lysosomal pH and to enable the lysosomal escape of drugs. Lysosomal escape may be associated with oxidative stress, permeabilization of the unstable membrane of cancer cell lysosomes, release of lysosomal enzymes into the cytoplasm, and cell death. GNMs can prevent or stimulate tumor cell death by inducing protective autophagy or suppressing autolysosomal degradation, respectively. Furthermore, because GNMs prevent bound fluorescent agents from emitting light, their separation in lysosomes may enable tumor cell identification and therapy monitoring. In this review, we explain how the characteristics of the lysosomal microenvironment and the unique features of tumor cell lysosomes can be exploited for GNM-based cancer therapy. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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17 pages, 3017 KiB

Open AccessReview

Shining a Light on Prostate Cancer: Photodynamic Therapy and Combination Approaches

by Hicham Wahnou, Ibtissam Youlyouz-Marfak, Bertrand Liagre, Vincent Sol, Mounia Oudghiri, Raphaël Emmanuel Duval and Youness Limami

Pharmaceutics 2023, 15(6), 1767; https://doi.org/10.3390/pharmaceutics15061767 - 19 Jun 2023

Cited by 12 | Viewed by 4487

Abstract

Prostate cancer is a major health concern worldwide, and current treatments, such as surgery, radiation therapy, and chemotherapy, are associated with significant side effects and limitations. Photodynamic therapy (PDT) is a promising alternative that has the potential to provide a minimally invasive and [...] Read more.

Prostate cancer is a major health concern worldwide, and current treatments, such as surgery, radiation therapy, and chemotherapy, are associated with significant side effects and limitations. Photodynamic therapy (PDT) is a promising alternative that has the potential to provide a minimally invasive and highly targeted approach to treating prostate cancer. PDT involves the use of photosensitizers (PSs) that are activated by light to produce reactive oxygen species (ROS), which can induce tumor cell death. There are two main types of PSs: synthetic and natural. Synthetic PSs are classified into four generations based on their structural and photophysical properties, while natural PSs are derived from plant and bacterial sources. Combining PDT with other therapies, such as photothermal therapy (PTT), photoimmunotherapy (PIT), and chemotherapy (CT), is also being explored as a way to improve its efficacy. This review provides an overview of conventional treatments for prostate cancer, the underlying principles of PDT, and the different types of PSs used in PDT as well as ongoing clinical studies. It also discusses the various forms of combination therapy being explored in the context of PDT for prostate cancer, as well as the challenges and opportunities associated with this approach. Overall, PDT has the potential to provide a more effective and less invasive treatment option for prostate cancer, and ongoing research is aimed at improving its selectivity and efficacy in clinical settings. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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52 pages, 2818 KiB

Open AccessReview

Combination Therapy as a Promising Way to Fight Oral Cancer

by João P. N. Silva, Bárbara Pinto, Luís Monteiro, Patrícia M. A. Silva and Hassan Bousbaa

Pharmaceutics 2023, 15(6), 1653; https://doi.org/10.3390/pharmaceutics15061653 - 4 Jun 2023

Cited by 15 | Viewed by 2638

Abstract

Oral cancer is a highly aggressive tumor with invasive properties that can lead to metastasis and high mortality rates. Conventional treatment strategies, such as surgery, chemotherapy, and radiation therapy, alone or in combination, are associated with significant side effects. Currently, combination therapy has [...] Read more.

Oral cancer is a highly aggressive tumor with invasive properties that can lead to metastasis and high mortality rates. Conventional treatment strategies, such as surgery, chemotherapy, and radiation therapy, alone or in combination, are associated with significant side effects. Currently, combination therapy has become the standard practice for the treatment of locally advanced oral cancer, emerging as an effective approach in improving outcomes. In this review, we present an in-depth analysis of the current advancements in combination therapies for oral cancer. The review explores the current therapeutic options and highlights the limitations of monotherapy approaches. It then focuses on combinatorial approaches that target microtubules, as well as various signaling pathway components implicated in oral cancer progression, namely, DNA repair players, the epidermal growth factor receptor, cyclin-dependent kinases, epigenetic readers, and immune checkpoint proteins. The review discusses the rationale behind combining different agents and examines the preclinical and clinical evidence supporting the effectiveness of these combinations, emphasizing their ability to enhance treatment response and overcome drug resistance. Challenges and limitations associated with combination therapy are discussed, including potential toxicity and the need for personalized treatment approaches. A future perspective is also provided to highlight the existing challenges and possible resolutions toward the clinical translation of current oral cancer therapies. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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43 pages, 3157 KiB

Open AccessReview

Clinical Relevance of Targeted Therapy and Immune-Checkpoint Inhibition in Lung Cancer

by Gian Marco Leone, Saverio Candido, Alessandro Lavoro, Silvia Vivarelli, Giuseppe Gattuso, Daniela Calina, Massimo Libra and Luca Falzone

Pharmaceutics 2023, 15(4), 1252; https://doi.org/10.3390/pharmaceutics15041252 - 16 Apr 2023

Cited by 9 | Viewed by 2869

Abstract

Lung cancer (LC) represents the second most diagnosed tumor and the malignancy with the highest mortality rate. In recent years, tremendous progress has been made in the treatment of this tumor thanks to the discovery, testing, and clinical approval of novel therapeutic approaches. [...] Read more.

Lung cancer (LC) represents the second most diagnosed tumor and the malignancy with the highest mortality rate. In recent years, tremendous progress has been made in the treatment of this tumor thanks to the discovery, testing, and clinical approval of novel therapeutic approaches. Firstly, targeted therapies aimed at inhibiting specific mutated tyrosine kinases or downstream factors were approved in clinical practice. Secondly, immunotherapy inducing the reactivation of the immune system to efficiently eliminate LC cells has been approved. This review describes in depth both current and ongoing clinical studies, which allowed the approval of targeted therapies and immune-checkpoint inhibitors as standard of care for LC. Moreover, the present advantages and pitfalls of new therapeutic approaches will be discussed. Finally, the acquired importance of human microbiota as a novel source of LC biomarkers, as well as therapeutic targets to improve the efficacy of available therapies, was analyzed. Therapy against LC is increasingly becoming holistic, taking into consideration not only the genetic landscape of the tumor, but also the immune background and other individual variables, such as patient-specific gut microbial composition. On these bases, in the future, the research milestones reached will allow clinicians to treat LC patients with tailored approaches. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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24 pages, 1071 KiB

Open AccessReview

Highlighted Advances in Therapies for Difficult-To-Treat Brain Tumours Such as Glioblastoma

by Nuno Cruz, Manuel Herculano-Carvalho, Diogo Roque, Cláudia C. Faria, Rita Cascão, Hugo Alexandre Ferreira, Catarina Pinto Reis and Nuno Matela

Pharmaceutics 2023, 15(3), 928; https://doi.org/10.3390/pharmaceutics15030928 - 13 Mar 2023

Cited by 7 | Viewed by 3545

Abstract

Glioblastoma multiforme (GBM) remains a challenging disease, as it is the most common and deadly brain tumour in adults and has no curative solution and an overall short survival time. This incurability and short survival time means that, despite its rarity (average incidence [...] Read more.

Glioblastoma multiforme (GBM) remains a challenging disease, as it is the most common and deadly brain tumour in adults and has no curative solution and an overall short survival time. This incurability and short survival time means that, despite its rarity (average incidence of 3.2 per 100,000 persons), there has been an increased effort to try to treat this disease. Standard of care in newly diagnosed glioblastoma is maximal tumour resection followed by initial concomitant radiotherapy and temozolomide (TMZ) and then further chemotherapy with TMZ. Imaging techniques are key not only to diagnose the extent of the affected tissue but also for surgery planning and even for intraoperative use. Eligible patients may combine TMZ with tumour treating fields (TTF) therapy, which delivers low-intensity and intermediate-frequency electric fields to arrest tumour growth. Nonetheless, the blood–brain barrier (BBB) and systemic side effects are obstacles to successful chemotherapy in GBM; thus, more targeted, custom therapies such as immunotherapy and nanotechnological drug delivery systems have been undergoing research with varying degrees of success. This review proposes an overview of the pathophysiology, possible treatments, and the most (not all) representative examples of the latest advancements. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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16 pages, 428 KiB

Open AccessReview

In Silico Studies to Support Vaccine Development

by Leonor Saldanha, Ülo Langel and Nuno Vale

Pharmaceutics 2023, 15(2), 654; https://doi.org/10.3390/pharmaceutics15020654 - 15 Feb 2023

Cited by 13 | Viewed by 3012

Abstract

The progress that has been made in computer science positioned in silico studies as an important and well-recognized methodology in the drug discovery and development process. It has numerous advantages in terms of costs and also plays a huge impact on the way [...] Read more.

The progress that has been made in computer science positioned in silico studies as an important and well-recognized methodology in the drug discovery and development process. It has numerous advantages in terms of costs and also plays a huge impact on the way the research is conducted since it can limit the use of animal models leading to more sustainable research. Currently, human trials are already being partly replaced by in silico trials. EMA and FDA are both endorsing these studies and have been providing webinars and guidance to support them. For instance, PBPK modeling studies are being used to gather data on drug interactions with other drugs and are also being used to support clinical and regulatory requirements for the pediatric population, pregnant women, and personalized medicine. This trend evokes the need to understand the role of in silico studies in vaccines, considering the importance that these products achieved during the pandemic and their promising hope in oncology. Vaccines are safer than other current oncology treatments. There is a huge variety of strategies for developing a cancer vaccine, and some of the points that should be considered when designing the vaccine technology are the following: delivery platforms (peptides, lipid-based carriers, polymers, dendritic cells, viral vectors, etc.), adjuvants (to boost and promote inflammation at the delivery site, facilitating immune cell recruitment and activation), choice of the targeted antigen, the timing of vaccination, the manipulation of the tumor environment, and the combination with other treatments that might cause additive or even synergistic anti-tumor effects. These and many other points should be put together to outline the best vaccine design. The aim of this article is to perform a review and comprehensive analysis of the role of in silico studies to support the development of and design of vaccines in the field of oncology and infectious diseases. The authors intend to perform a literature review of all the studies that have been conducted so far in preparing in silico models and methods to support the development of vaccines. From this point, it was possible to conclude that there are few in silico studies on vaccines. Despite this, an overview of how the existing work could support the design of vaccines is described. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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22 pages, 1701 KiB

Open AccessReview

Anticancer Applications of Essential Oils Formulated into Lipid-Based Delivery Nanosystems

by Josef Jampilek and Katarina Kralova

Pharmaceutics 2022, 14(12), 2681; https://doi.org/10.3390/pharmaceutics14122681 - 1 Dec 2022

Cited by 16 | Viewed by 3053

Abstract

The use of natural compounds is becoming increasingly popular among patients, and there is a renewed interest among scientists in nature-based bioactive agents. Traditionally, herbal drugs can be taken directly in the form of teas/decoctions/infusions or as standardized extracts. However, the disadvantages of [...] Read more.

The use of natural compounds is becoming increasingly popular among patients, and there is a renewed interest among scientists in nature-based bioactive agents. Traditionally, herbal drugs can be taken directly in the form of teas/decoctions/infusions or as standardized extracts. However, the disadvantages of natural compounds, especially essential oils, are their instability, limited bioavailability, volatility, and often irritant/allergenic potential. However, these active substances can be stabilized by encapsulation and administered in the form of nanoparticles. This brief overview summarizes the latest results of the application of nanoemulsions, liposomes, solid lipid nanoparticles, and nanostructured lipid carriers used as drug delivery systems of herbal essential oils or used directly for their individual secondary metabolites applicable in cancer therapy. Although the discussed bioactive agents are not typical compounds used as anticancer agents, after inclusion into the aforesaid formulations improving their stability and bioavailability and/or therapeutic profile, they indicated anti-tumor activity and became interesting agents with cancer treatment potential. In addition, co-encapsulation of essential oils with synthetic anticancer drugs into nanoformulations with the aim to achieve synergistic effect in chemotherapy is discussed. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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