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Cancer Prevention with Molecular Target Therapies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (16 November 2020) | Viewed by 60863

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Dr. Laura Paleari

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Research, Innovation and HTA Unit, (A.Li.Sa.) Liguria Health Authority, 16121 Genoa, Italy
Interests: cancer prevention; molecular biology; drug repurposing; health technology assessment; pharmacoeconomics
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Special Issue Information

Dear Colleagues,

Personalized medicine is playing an important role in cancer prevention. To date, it is clear that many cancers are molecularly distinct subtypes, and different therapeutic approaches would be required for each. Indeed, the identification of cancer susceptibility genes permits identifying patients “at risk” of developing neoplasia and supports modifying individual risk behaviors or the choice of preventive therapy. Additionally, the efficacy of various targeted therapies in different cancer subtypes suggests that treatment choices in a near future will be more and more centered on molecular signatures. Data from preclinical, clinical, and observational studies have revealed the ability to prevent cancer development for compounds with different indications than cancer. The concept of drug repurposing permits combinations that can target several critical pathways of a specific disease, decreasing the risk of resistance observed when using single agent targeted therapy.

This open-access Special Issue will bring together original research and review articles on molecular oncology with attention to early detection and prevention of cancer. It highlights new findings, methods, and technical advances in molecular cancer research. The main feature of this Special Issue is to provide an open-source sharing of significant works in the field of molecular oncology that can increase our understanding of cancer development, which may lead to the discovery of new molecular diagnostic technologies and targeted therapeutics.

Topics include but are not limited to:

1—Molecular methods to personalize cancer screening and detection;

2—Molecular target therapies to prevent cancer development and metastases;

3—Identification and new aspects of cellular signaling molecules and pathways for target discovery, drug design, and personalized and gender medicine;

4—Drug repurposing for cancer prevention;

5—Molecular modeling studies.

Dr. Laura Paleari
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Cancer prevention
Target therapy
Personalized screening
Drug repurposing
Target discovery

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Published Papers (12 papers)

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Research

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16 pages, 1096 KiB

Open AccessArticle

Survival of Lung Cancer Patients Dependent on the LOH Status for DMP1, ARF, and p53

by Elizabeth A. Fry, Gloria E. Niehans, Robert A. Kratzke, Fumitake Kai and Kazushi Inoue

Int. J. Mol. Sci. 2020, 21(21), 7971; https://doi.org/10.3390/ijms21217971 - 27 Oct 2020

Cited by 3 | Viewed by 2123

Abstract

Lung cancer is the leading cause of cancer deaths in the world, and accounts for more solid tumor deaths than any other carcinomas. The prognostic values of DMP1, ARF, and p53-loss are unknown in lung cancer. We have conducted survival analyses of non-small cell lung cancer (NSCLC) patients from the University of Minnesota VA hospital and those from the Wake Forest University Hospital. Loss of Heterozygosity (LOH) for hDMP1 was found in 26 of 70 cases (37.1%), that of the ARF/INK4a locus was found in 33 of 70 (47.1%), and that of the p53 locus in 43 cases (61.4%) in the University of Minnesota samples. LOH for hDMP1 was associated with favorable prognosis while that of p53 predicted worse prognosis. The survival was much shorter for ARF-loss than INK4a-loss, emphasizing the importance of ARF in human NSCLC. The adverse effect of p53 LOH on NSCLC patients’ survival was neutralized by simultaneous loss of the hDMP1 locus in NSCLC and breast cancer, suggesting the possible therapy of epithelial cancers with metastatic ability. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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21 pages, 3202 KiB

Open AccessArticle

A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells

by Gaetano Marverti, Gaia Gozzi, Eleonora Maretti, Angela Lauriola, Leda Severi, Francesca Sacchetti, Lorena Losi, Salvatore Pacifico, Stefania Ferrari, Glauco Ponterini, Eliana Leo, Maria Paola Costi and Domenico D’Arca

Int. J. Mol. Sci. 2020, 21(12), 4452; https://doi.org/10.3390/ijms21124452 - 23 Jun 2020

Cited by 6 | Viewed by 3127

Abstract

There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance to the hTS inhibitors 5-fluorouracil (5-FU) and raltitrexed (RTX). In the present work, we propose a new tool to combat drug resistance. We propose to treat OC cell lines, both Pt-sensitive and -resistant, with dual combinations of one of the four chemotherapeutic agents that are widely used in the clinic, and the new peptide, hTS inhibitor, [D-Gln⁴]LR. This binds hTS allosterically and, unlike classical inhibitors that bind at the catalytic pocket, causes cell growth inhibition without inducing hTS overexpression. The dual drug combinations showed schedule-dependent synergistic antiproliferative and apoptotic effects. We observed that the simultaneous treatment or 24h pre-treatment of OC cells with the peptide followed by either agent produced synergistic effects even in resistant cells. Similar synergistic or antagonistic effects were obtained by delivering the peptide into OC cells either by means of a commercial delivery system (SAINT-PhD) or by pH sensitive PEGylated liposomes. Relative to non-PEGylated liposomes, the latter had been previously characterized and found to allow macrophage escape, thus increasing their chance to reach the tumour tissue. The transition from the SAINT-PhD delivery system to the engineered liposomes represents an advancement towards a more drug-like delivery system and a further step towards the use of peptides for in vivo studies. Overall, the results suggest that the association of standard drugs, such as cDDP and/or 5-FU and/or RTX, with the novel peptidic TS inhibitor encapsulated into PEGylated pH-sensitive liposomes can represent a promising strategy for fighting resistance to cDDP and anti-hTS drugs. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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10 pages, 4563 KiB

Open AccessArticle

Phosphodiesterase SMPDL3B Gene Expression as Independent Outcome Prediction Marker in Localized Prostate Cancer

by Frank Waldbillig, Katja Nitschke, Abdallah Abdelhadi, Jost von Hardenberg, Philipp Nuhn, Malin Nientiedt, Cleo-Aron Weis, Maurice Stephan Michel, Philipp Erben and Thomas Stefan Worst

Int. J. Mol. Sci. 2020, 21(12), 4373; https://doi.org/10.3390/ijms21124373 - 19 Jun 2020

Cited by 7 | Viewed by 2506

Abstract

Current outcome prediction markers for localized prostate cancer (PCa) are insufficient. The impact of the lipid-modifying Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3B) in PCa is unknown. Two cohorts of patients with PCa who underwent radical prostatectomy (n = 40, n = 56) and benign prostate hyperplasia (BPH) controls (n = 8, n = 11) were profiled for SMPDL3B expression with qRT-PCR. Publicly available PCa cohorts (Memorial Sloane Kettering Cancer Centre (MSKCC; n = 131, n = 29 controls) and The Cancer Genome Atlas (TCGA; n = 497, n = 53 controls)) served for validation. SMPDL3B’s impact on proliferation and migration was analyzed in PC3 cells by siRNA knockdown. In both cohorts, a Gleason score and T stage independent significant overexpression of SMPDL3B was seen in PCa compared to BPH (p < 0.001 each). A lower expression of SMPDL3B was associated with a shorter overall survival (OS) (p = 0.005) in long term follow-up. A SMPDL3B overexpression in PCa tissue was confirmed in the validation cohorts (p < 0.001 each). In the TCGA patients with low SMPDL3B expression, biochemical recurrence-free survival (p = 0.011) and progression-free interval (p < 0.001) were shorter. Knockdown of SMPDL3B impaired PC3 cell migration but not proliferation (p = 0.0081). In summary, SMPLD3B is highly overexpressed in PCa tissue, is inversely associated with localized PCa prognosis, and impairs PCa cell migration. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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14 pages, 2726 KiB

Open AccessArticle

Hedgehog Signal Inhibitor GANT61 Inhibits the Malignant Behavior of Undifferentiated Hepatocellular Carcinoma Cells by Targeting Non-Canonical GLI Signaling

by Kensuke Harada, Ryuya Ohashi, Kyoko Naito and Keita Kanki

Int. J. Mol. Sci. 2020, 21(9), 3126; https://doi.org/10.3390/ijms21093126 - 28 Apr 2020

Cited by 24 | Viewed by 3666

Abstract

The Hedgehog (HH)–GLI pathway plays an important role in cell dedifferentiation and is therefore pivotally involved in the malignant transformation of cancer cells. GANT61, a selective inhibitor of GLI1 and GLI2, was reported as a promising treatment for cancer in various tissues; however, the biological impact of GANT61 in hepatocellular carcinoma (HCC), especially in undifferentiated HCC cells, remains unclear. In this study, we investigated the antitumor effect of GANT61 using two undifferentiated hepatoma cell lines: HLE and HLF. Quantitative PCR and RT-PCR analyses revealed that these cells express GLI transcripts, showing mesenchymal phenotypes characterized by the loss of epithelial and hepatic markers and specific expression of epithelial–mesenchymal transition (EMT)-related genes. GANT61 significantly reduced the proliferation and cell viability after drug treatment using 5-FU and Mitomycin C. We showed that GLI transcript levels were down-regulated by the MEK inhibitor U0126 and the Raf inhibitor sorafenib, suggesting that non-canonical signaling including the Ras–Raf–MEK–ERK pathway is involved. Sphere formation and migration were significantly decreased by GANT61 treatment, and it is suggested that the underlying molecular mechanisms are the down-regulation of stemness-related genes (Oct4, Bmi1, CD44, and ALDH) and the EMT-related gene Snail1. The data presented here showed that direct inhibition of GLI might be beneficial for the treatment of dedifferentiated HCC. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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13 pages, 1475 KiB

Open AccessArticle

Efficacy of Immune Checkpoint Inhibitor Monotherapy for Advanced Non-Small-Cell Lung Cancer with ALK Rearrangement

by Yuko Oya, Hiroaki Kuroda, Takeo Nakada, Yusuke Takahashi, Noriaki Sakakura and Toyoaki Hida

Int. J. Mol. Sci. 2020, 21(7), 2623; https://doi.org/10.3390/ijms21072623 - 9 Apr 2020

Cited by 33 | Viewed by 4987

Abstract

Programmed death-ligand 1 (PD-L1) expression is a predictor of immune checkpoint inhibitor (ICI) treatment efficacy. The clinical efficacy of ICIs for non-small-cell lung cancer (NSCLC) patients harboring major mutations, such as EGFR or ALK mutations, is limited. We genotyped 190 patients with advanced lung adenocarcinomas who received nivolumab or pembrolizumab monotherapy, and examined the efficacy in NSCLC patients with or without major mutations. Among the patients enrolled in the genotyping study, 47 patients harbored EGFR mutations, 25 patients had KRAS mutations, 5 patients had a HER2 mutation, 6 patients had a BRAF mutation, and 7 patients had ALK rearrangement. The status of PD-L1 expression was evaluated in 151 patients, and the rate of high PD-L1 expression (≥50%) was significantly higher in patients with ALK mutations. The progression-free survival was 0.6 (95% CI: 0.2–2.1) months for ALK-positive patients and 1.8 (95% CI: 1.2–2.1) months for EGFR-positive patients. All patients with ALK rearrangement showed disease progression within three months from the initiation of anti-PD-1 treatment. Our data suggested that ICI treatment was significantly less efficacious in patients with ALK rearrangement than in patients with EGFR mutations, and PD-L1 expression was not a critical biomarker for ICI treatment for patients with one of these mutations. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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8 pages, 545 KiB

Open AccessArticle

Aromatase Inhibitors as Adjuvant Treatment for ER/PgR Positive Stage I Endometrial Carcinoma: A Retrospective Cohort Study

by Laura Paleari, Mariangela Rutigliani, Giacomo Siri, Nicoletta Provinciali, Nicoletta Colombo and Andrea Decensi

Int. J. Mol. Sci. 2020, 21(6), 2227; https://doi.org/10.3390/ijms21062227 - 23 Mar 2020

Cited by 9 | Viewed by 2591

Abstract

Objective: Although endometrial cancer (EC) is a hormone dependent neoplasm, there are no recommendations for the determination of steroid hormone receptors in the tumor tissue and no hormone therapy has ever been assessed in the adjuvant setting. The purpose of this study was to explore the effect of adjuvant aromatase inhibitors (AIs) on progression-free survival (PFS) and overall survival (OS) in patients with early stage and steroid receptors-positive EC. Methods: We retrospectively analyzed clinical and pathological factors in 73 patients with high-risk (49.3%) or low-risk (50.7%) stage I (n = 71) or II (n = 2) endometrial cancer who received by their preference after counseling either no treatment (reference group) or AI. Prognostic factors were well balanced between groups. Expression of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 index was correlated with clinical outcomes. Results: Univariate and multivariate Cox proportional regression analyses, adjusted for age, grade, stage, depth of myometrial invasion, lymphovascular space invasion, BMI, ER, PgR and Ki-67 labeling index levels, showed that PFS and OS had a trend to be longer in patients receiving AI than in the reference group HR= 0.23 (95% CI; 0.04–1.27) for PFS and HR= 0.11 (95% CI; 0.01–1.36) for OS. Conclusion: Compared with no treatment, AI exhibited a trend toward a benefit on PFS and OS in patients with early stage hormone receptor-positive EC. Given the exploratory nature of our study, randomized clinical trials for ER/PgR positive EC patients are warranted to assess the clinical benefit of AI and the potential predictive role of steroid receptors and Ki-67. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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9 pages, 1485 KiB

Open AccessCommunication

Beta3-Tubulin Is Critical for Microtubule Dynamics, Cell Cycle Regulation, and Spontaneous Release of Microvesicles in Human Malignant Melanoma Cells (A375)

by Mohammed O. Altonsy, Anutosh Ganguly, Matthias Amrein, Philip Surmanowicz, Shu Shun Li, Gilles J. Lauzon and P. Régine Mydlarski

Int. J. Mol. Sci. 2020, 21(5), 1656; https://doi.org/10.3390/ijms21051656 - 28 Feb 2020

Cited by 17 | Viewed by 4002

Abstract

Microtubules (MTs), microfilaments, and intermediate filaments, the main constituents of the cytoskeleton, undergo continuous structural changes (metamorphosis), which are central to cellular growth, division, and release of microvesicles (MVs). Altered MTs dynamics, uncontrolled proliferation, and increased production of MVs are hallmarks of carcinogenesis. Class III beta-tubulin (β3-tubulin), one of seven β-tubulin isotypes, is a primary component of MT, which correlates with enhanced neoplastic cell survival, metastasis and resistance to chemotherapy. We studied the effects of β3-tubulin gene silencing on MTs dynamics, cell cycle, and MVs release in human malignant melanoma cells (A375). The knockdown of β3-tubulin induced G2/M cell cycle arrest, impaired MTs dynamics, and reduced spontaneous MVs release. Additional studies are therefore required to elucidate the pathophysiologic and therapeutic role of β3-tubulin in melanoma. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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Review

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25 pages, 874 KiB

Open AccessReview

The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy

by Manlio Tolomeo and Antonio Cascio

Int. J. Mol. Sci. 2021, 22(2), 603; https://doi.org/10.3390/ijms22020603 - 9 Jan 2021

Cited by 171 | Viewed by 8457

Abstract

Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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12 pages, 709 KiB

Open AccessReview

Targeted Therapies in Early Stage NSCLC: Hype or Hope?

by Alex Friedlaender, Alfredo Addeo, Alessandro Russo, Vanesa Gregorc, Diego Cortinovis and Christian D. Rolfo

Int. J. Mol. Sci. 2020, 21(17), 6329; https://doi.org/10.3390/ijms21176329 - 31 Aug 2020

Cited by 74 | Viewed by 9838

Abstract

Non-small-cell lung cancer (NSCLC) represents roughly 85% of lung cancers, with an incidence that increases yearly across the world. The introduction in clinical practice of several new and more effective molecules has led to a consistent improvement in survival and quality of life in locally advanced and metastatic NSCLC. In particular, oncogenic drivers have indeed transformed the therapeutic algorithm for NSCLC. Nearly 25% of patients are diagnosed in an early stage when NSCLC is still amenable to radical surgery. In spite of this, five-year survival rates for fully resected early stage remains rather disappointing. Adjuvant chemotherapy has shown a modest survival benefit depending on the stage, but more than half of patients relapse. Given this need for improvement, over the last years different targeted therapies have been evaluated in early-stage NSCLC with no survival benefit in unselected patients. However, the identification of reliable predictive biomarkers to these agents in the metastatic setting, the design of molecularly-oriented studies, and the availability of novel potent and less toxic agents opened the way for a novel era in early stage NSCLC treatment. In this review, we will discuss the current landscape of targeted therapeutic options in early NSCLC. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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20 pages, 2179 KiB

Open AccessReview

Microbiota-Associated Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Cancer: A Review

by Yi-Hsun Chen, Wei-Kai Wu and Ming-Shiang Wu

Int. J. Mol. Sci. 2020, 21(17), 5999; https://doi.org/10.3390/ijms21175999 - 20 Aug 2020

Cited by 17 | Viewed by 5036

Abstract

Even though advancement in medicine has contributed to the control of many diseases to date, cancer therapy continues to pose several challenges. Hepatocellular carcinoma (HCC) etiology is multifactorial. Recently, non-alcoholic fatty liver disease (NAFLD) has been considered as an important risk factor of HCC. NAFLD can be divided into non-alcoholic simple fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) based on histopathological features. Recently, studies have indicated that the gut microbiota is associated with NAFLD and HCC. Therefore, in this review, we have discussed the effects of gut microbiota-related mechanisms, including dysbiosis and gut barrier function, and gut microbiota-derived metabolites on NAFLD and HCC pathogenesis and the potential therapeutic strategies for NAFLD and HCC. With a better understanding of the gut microbiota composition and function, new and improved diagnostic, prognostic, and therapeutic strategies for common liver diseases can be developed. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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25 pages, 656 KiB

Open AccessReview

Evolution of Urothelial Bladder Cancer in the Context of Molecular Classifications

by Martina Minoli, Mirjam Kiener, George N. Thalmann, Marianna Kruithof-de Julio and Roland Seiler

Int. J. Mol. Sci. 2020, 21(16), 5670; https://doi.org/10.3390/ijms21165670 - 7 Aug 2020

Cited by 58 | Viewed by 8710

Abstract

Bladder cancer is a heterogeneous disease that is not depicted by current classification systems. It was originally classified into non-muscle invasive and muscle invasive. However, clinically and genetically variable tumors are summarized within both classes. A definition of three groups may better account for the divergence in prognosis and probably also choice of treatment. The first group represents mostly non-invasive tumors that reoccur but do not progress. Contrarily, the second group represent non-muscle invasive tumors that likely progress to the third group, the muscle invasive tumors. High throughput tumor profiling improved our understanding of the biology of bladder cancer. It allows the identification of molecular subtypes, at least three for non-muscle invasive bladder cancer (Class I, Class II and Class III) and six for muscle-invasive bladder cancer (luminal papillary, luminal non-specified, luminal unstable, stroma-rich, basal/squamous and neuroendocrine-like) with distinct clinical and molecular phenotypes. Molecular subtypes can be potentially used to predict the response to treatment (e.g., neoadjuvant chemotherapy and immune checkpoint inhibitors). Moreover, they may allow to characterize the evolution of bladder cancer through different pathways. However, to move towards precision medicine, the understanding of the biological meaning of these molecular subtypes and differences in the composition of cell subpopulations will be mandatory. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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19 pages, 1905 KiB

Open AccessReview

Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration

by Maria Krchniakova, Jan Skoda, Jakub Neradil, Petr Chlapek and Renata Veselska

Int. J. Mol. Sci. 2020, 21(9), 3157; https://doi.org/10.3390/ijms21093157 - 30 Apr 2020

Cited by 35 | Viewed by 4970

Abstract

Tyrosine kinase inhibitors (TKIs) are being increasingly used to treat various malignancies. Although they were designed to target aberrant tyrosine kinases, they are also intimately linked with the mechanisms of multidrug resistance (MDR) in cancer cells. MDR-related solute carrier (SLC) and ATB-binding cassette (ABC) transporters are responsible for TKI uptake and efflux, respectively. However, the role of TKIs appears to be dual because they can act as substrates and/or inhibitors of these transporters. In addition, several TKIs have been identified to be sequestered into lysosomes either due to their physiochemical properties or via ABC transporters expressed on the lysosomal membrane. Since the development of MDR represents a great concern in anticancer treatment, it is important to elucidate the interactions of TKIs with MDR-related transporters as well as to improve the properties that would prevent TKIs from diffusing into lysosomes. These findings not only help to avoid MDR, but also help to define the possible impact of combining TKIs with other anticancer drugs, leading to more efficient therapy and fewer adverse effects in patients. Full article

(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)

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