Identification of Novel Compounds against Multidrug-Resistant Cancer Cells

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 October 2021) | Viewed by 4888

Special Issue Editors


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Guest Editor
Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
Interests: cancer biology; bioinformatics; multidrug resistance; artificial intelligence; virtual screening; compound identification targeting cancer progression

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Guest Editor
Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
Interests: natural products; molecular pharmacology; cancer; drug resistance; genome-wide profiling
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Special Issue Information

Dear Colleagues,

Multidrug resistance (MDR) is among the major reasons for chemotherapy failure and cancer progression. In addition to ATP-binding cassette (ABC) transporters, various additional mechanisms are involved in which the tumour cells arrange themselves and continue to proliferate even in the presence of chemotherapy drugs. This leads to increased metastasis potential as well. Targeting those MDR mechanisms is of utmost importance for establishing effective and novel chemotherapy strategies. Established chemotherapy drugs such as doxorubicin, docetaxel, and cisplatin are insufficient to kill those tumour cells with MDR phenotypes. Inhibitors of ABC transporters can increase the efficiency of chemotherapy to some extent, but because of the multifactorial nature of MDR phenomena, novel inhibitors to target different MDR mechanisms are required. For this purpose, various MDR-associated proteins are awaiting targeting with natural compounds or synthetic derivatives to identify novel inhibitors to overcome MDR phenomena and increase chemotherapy success rates.

This special issue of Pharmaceuticals on the “Identification of Novel Compounds against Multidrug-Resistant Cancer Cells” will include both regular articles and reviews focused on the most recent advances in the identification of novel compounds against multidrug-resistant cancer cells. The utilization of artificial intelligence, the establishment of predictive models, and virtual screenings are also valuable for identifying potential inhibitors of various MDR-associated proteins.

Dr. Onat Kadioglu
Prof. Dr. Thomas Efferth
Guest Editors

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Keywords

  • Multidrug resistance
  • Cancer progression
  • Novel compounds against cancer
  • Artificial intelligence
  • Virtual screening
  • Natural compounds
  • Synthetic compounds
  • Inhibitors
  • Tumorigenesis
  • Chemotherapy failure
  • Overcoming drug resistance.

Published Papers (2 papers)

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Research

13 pages, 2171 KiB  
Article
Identification of Novel Anthracycline Resistance Genes and Their Inhibitors
by Onat Kadioglu, Mohamed Elbadawi, Edmond Fleischer and Thomas Efferth
Pharmaceuticals 2021, 14(10), 1051; https://doi.org/10.3390/ph14101051 - 16 Oct 2021
Cited by 2 | Viewed by 2352
Abstract
Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA [...] Read more.
Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA were overexpressed by lentiviral-plasmid-based transfection of HEK293 cells. An in silico drug repurposing approach was applied using virtual screening and molecular docking of FDA-approved drugs to identify inhibitors of these new drug-resistant genes. Overexpression of the selected genes conferred resistance to doxorubicin and daunorubicin but not to vincristine, docetaxel, and cisplatin, indicating the involvement of these genes in resistance to anthracyclines but not to a broader MDR phenotype. Using virtual drug screening and molecular docking analyses, we identified FDA-approved compounds (conivaptan, bexarotene, and desloratadine) that were interacting with HMOX1 and PRKCA at even stronger binding affinities than 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethenone and ellagic acid as known inhibitors of HMOX1 and PRKCA, respectively. Conivaptan treatment increased doxorubicin sensitivity of both HMOX1- and PRKCA-transfected cell lines. Bexarotene treatment had a comparable doxorubicin-sensitizing effect in HMOX1-transfected cells and desloratadine in PRKCA-transfected cells. Novel drug resistance mechanisms independent of ABC transporters have been identified that contribute to anthracycline resistance in MDR cells. Full article
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16 pages, 2398 KiB  
Article
Chemoreversal Agents from Taiwanofungus Genus and Their More Potent Methyl Derivatives Targeting Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation
by Ko-Hua Yu, Chin-Chuan Hung, Tian-Shung Wu, Chin-Fu Chen, I-Ting Wu, Ping-Chung Kuo, Sio-Hong Lam and Hsin-Yi Hung
Pharmaceuticals 2021, 14(9), 916; https://doi.org/10.3390/ph14090916 - 10 Sep 2021
Viewed by 1620
Abstract
Multidrug resistance (MDR), for which the mechanisms are not yet fully clear, is one of the major obstacles to cancer treatment. In recent years, signal transducer and activator of transcription 3 (STAT3) were found to be one of the important MDR mechanism pathways. [...] Read more.
Multidrug resistance (MDR), for which the mechanisms are not yet fully clear, is one of the major obstacles to cancer treatment. In recent years, signal transducer and activator of transcription 3 (STAT3) were found to be one of the important MDR mechanism pathways. Based on the previous research, zhankuic acid A, B, and C were found to have collateral sensitivity effects on MDR cancer cells, and MDR inhibitory activity of zhankuic acid methyl ester was found to be better than that of its acid. Therefore, we executed a systematic examination of the structure–activity relationship of zhankuic acid methyl ester derivatives to collateral sensitivity in MDR cancer cells. The results showed that compound 12 is the best in terms of chemoreversal activity, where the reversal fold was 692, and the IC50 value of paclitaxel combined with 10 μM compound 12 treatment was 1.69 nM in MDR KBvin cells. Among all the derivatives, methyl ester compounds were found to be better than their acids, and a detailed discussion of the structure–activity relationships of all of the derivatives is provided in this work. In addition, compounds 8, 12, and 26 were shown to influence the activation of STAT3 in KBvin cells, accounting for part of their chemoreversal effects. Our results may provide a new combined therapy with paclitaxel to treat multidrug-resistant cancers and provide a new therapy option for patients. Full article
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