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Multidrug Resistance in Cancer: Molecular Mechanisms and Therapeutic Implications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 4643

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Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy
Interests: prostate cancer; melanoma; ovarian cancer; cancer biology; mechanisms of cancer cell death; cancer metastasis; cancer metabolism; cancer drug resistance; cancer stem cells; tumor microenvironment; extracellular vesicles
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Special Issue Information

Dear Colleagues,

Drug resistance still represents the main reason for therapy failure in cancer patients. Indeed, despite being initially susceptible to standard strategies, tumor cells frequently become irresponsive to current treatments via different mechanisms that can impair drug efficacy, including reduced drug adsorption, increased DNA repair and cell death suppression, gene mutation and amplification, and epigenetic changes. Other key processes frequently involved in reduction in drug sensitivity are based on cancer stem cell selection and survival, as well as on the complex interaction network occurring in the tumor microenvironment. More recently, the crucial role of the gut microbiome in cancer recurrence has also been highlighted.

Based on these premises, several efforts have been directed toward the identification of new biomarkers able to predict therapeutic outcomes: circulating cancer cells, as well as circulating tumor DNA, cancer cell secretome, and tumor-derived extracellular vesicles and miRNAs can be easily isolated from patient body fluids. On the other hand, novel therapeutic approaches, involving both synthetic and natural compounds, are being developed to overcome drug resistance.

The aim of this Special Issue is to publish original articles and reviews in the field of basic and translational cancer research that specifically addresses the above topics, leading to the discovery of new molecular pathways and biomarkers associated with chemoresistance, as well as to the definition of novel drug combinations that could prevent tumor relapse.

Dr. Fabrizio Fontana
Guest Editor

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Keywords

  • cancer drug resistance
  • cancer stem cells
  • tumor microenvironment
  • gut microbiome
  • cancer secretome
  • extracellular vesicles
  • -omics
  • biomarkers
  • combination therapies

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Published Papers (3 papers)

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Research

16 pages, 4980 KiB  
Communication
Short Communication: Novel Di- and Triselenoesters as Effective Therapeutic Agents Inhibiting Multidrug Resistance Proteins in Breast Cancer Cells
by Dominika Radomska, Robert Czarnomysy, Krzysztof Marciniec, Justyna Nowakowska, Enrique Domínguez-Álvarez and Krzysztof Bielawski
Int. J. Mol. Sci. 2024, 25(17), 9732; https://doi.org/10.3390/ijms25179732 - 8 Sep 2024
Viewed by 1029
Abstract
Breast cancer has the highest incidence rate among all malignancies worldwide. Its high mortality is mainly related to the occurrence of multidrug resistance, which significantly limits therapeutic options. In this regard, there is an urgent need to develop compounds that would overcome this [...] Read more.
Breast cancer has the highest incidence rate among all malignancies worldwide. Its high mortality is mainly related to the occurrence of multidrug resistance, which significantly limits therapeutic options. In this regard, there is an urgent need to develop compounds that would overcome this phenomenon. There are few reports in the literature that selenium compounds can modulate the activity of P-glycoprotein (MDR1). Therefore, we performed in silico studies and evaluated the effects of the novel selenoesters EDAG-1 and EDAG-8 on BCRP, MDR1, and MRP1 resistance proteins in MCF-7 and MDA-MB-231 breast cancer cells. The cytometric analysis showed that the tested compounds (especially EDAG-8) are inhibitors of BCRP, MDR1, and MRP1 efflux pumps (more potent than the reference compounds—novobiocin, verapamil, and MK-571). An in silico study correlates with these results, suggesting that the compound with the lowest binding energy to these transporters (EDAG-8) has a more favorable spatial structure affecting its anticancer activity, making it a promising candidate in the development of a novel anticancer agent for future breast cancer therapy. Full article
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11 pages, 3091 KiB  
Article
ABCG2 Mediates Resistance to the Dual EGFR and PI3K Inhibitor MTX-211 in Cancer Cells
by Chung-Pu Wu, Cheng-Yu Hung, Megumi Murakami, Yu-Shan Wu, Yi-Hsuan Chu, Yang-Hui Huang, Jau-Song Yu and Suresh V. Ambudkar
Int. J. Mol. Sci. 2024, 25(10), 5160; https://doi.org/10.3390/ijms25105160 - 9 May 2024
Cited by 1 | Viewed by 1125
Abstract
MTX-211 is a first-in-class dual inhibitor of epidermal growth factor receptor (EGFR) and phosphoinositide-3 kinase (PI3K) signaling pathways with a compelling pharmaceutical profile and could enhance the effectiveness of mitogen-activated protein kinase kinase (MEK) inhibitor therapy in colorectal tumors with KRAS mutations. However, [...] Read more.
MTX-211 is a first-in-class dual inhibitor of epidermal growth factor receptor (EGFR) and phosphoinositide-3 kinase (PI3K) signaling pathways with a compelling pharmaceutical profile and could enhance the effectiveness of mitogen-activated protein kinase kinase (MEK) inhibitor therapy in colorectal tumors with KRAS mutations. However, the specific mechanisms contributing to the acquired resistance to MTX-211 in human cancers remain elusive. Here, we discovered that the overexpression of the ATP-binding cassette (ABC) drug transporter ABCG2, a prevalent mechanism associated with multidrug resistance (MDR), could diminish the effectiveness of MTX-211 in human cancer cells. We showed that the drug efflux activity of ABCG2 substantially decreased the intracellular accumulation of MTX-211 in cancer cells. As a result, the cytotoxicity and effectiveness of MTX-211 in suppressing the activation of the EGFR and PI3K pathways were significantly attenuated in cancer cells overexpressing ABCG2. Moreover, the enhancement of the MTX-211-stimulated ATPase activity of ABCG2 and the computational molecular docking analysis illustrating the binding of MTX-211 to the substrate-binding sites of ABCG2 offered a further indication for the interaction between MTX-211 and ABCG2. In summary, our findings indicate that MTX-211 acts as a substrate for ABCG2, underscoring the involvement of ABCG2 in the emergence of resistance to MTX-211. This finding carries clinical implications and merits further exploration. Full article
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18 pages, 6360 KiB  
Article
Furmonertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, Overcomes Multidrug Resistance through Inhibiting ABCB1 and ABCG2 in Cancer Cells
by Chung-Pu Wu, Yen-Ching Li, Megumi Murakami, Sung-Han Hsiao, Yun-Chieh Lee, Yang-Hui Huang, Yu-Tzu Chang, Tai-Ho Hung, Yu-Shan Wu and Suresh V. Ambudkar
Int. J. Mol. Sci. 2023, 24(18), 13972; https://doi.org/10.3390/ijms241813972 - 12 Sep 2023
Cited by 3 | Viewed by 1979
Abstract
ATP-binding cassette transporters, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP/MXR/ABCP), are pivotal in multidrug resistance (MDR) development in cancer patients undergoing conventional chemotherapy. The absence of approved therapeutic agents for multidrug-resistant cancers presents a significant challenge in effectively treating cancer. Researchers propose repurposing existing [...] Read more.
ATP-binding cassette transporters, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP/MXR/ABCP), are pivotal in multidrug resistance (MDR) development in cancer patients undergoing conventional chemotherapy. The absence of approved therapeutic agents for multidrug-resistant cancers presents a significant challenge in effectively treating cancer. Researchers propose repurposing existing drugs to sensitize multidrug-resistant cancer cells, which overexpress ABCB1 or ABCG2, to conventional anticancer drugs. The goal of this study is to assess whether furmonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor overcomes drug resistance mediated by ABCB1 and ABCG2 transporters. Furmonertinib stands out due to its ability to inhibit drug transport without affecting protein expression. The discovery of this characteristic was validated through ATPase assays, which revealed interactions between furmonertinib and ABCB1/ABCG2. Additionally, in silico docking of furmonertinib offered insights into potential interaction sites within the drug-binding pockets of ABCB1 and ABCG2, providing a better understanding of the underlying mechanisms responsible for the reversal of MDR by this repurposed drug. Given the encouraging results, we propose that furmonertinib should be explored as a potential candidate for combination therapy in patients with tumors that have high levels of ABCB1 and/or ABCG2. This combination therapy holds the potential to enhance the effectiveness of conventional anticancer drugs and presents a promising strategy for overcoming MDR in cancer treatment. Full article
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