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Drug Resistance-Associated Proteins in Cancer
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Drug Resistance-Associated Proteins in Cancer

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

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 14964

Special Issue Editors

Prof. Dr. Takeo Nakanishi

E-Mail Website
Guest Editor
Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-shi 370-0033, Japan
Interests: cancer; chemotherapy; drug-resistance; pharmacology; transporter; gene expression; pharmacokinetics; inflammation; prostaglandin
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Zhe-Sheng (Jason) Chen

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
Interests: drug resistance; ABC transporter; tyrosine kinase inhibitor; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is one of the leading causes of death worldwide. Despite the development of efficient small molecules targeting oncogenic drivers, many patients relapse as treatment proceeds. Chemotherapy often fails because of drug resistance acquired by cancer cells, and therefore drug resistance remains an important obstacle to the successful treatment of cancer.

Current evidence suggests that various molecular mechanisms are involved in drug resistance, including increased cell antiapoptotic potential, enhanced DNA repairs, and altered drug metabolisms and transport. In particular, the activated export of anti-cancer drugs by drug efflux pumps causes multidrug resistance (MDR) and worsens the prognosis of cancer patients. Because individual genetic differences determine these biological processes, individual genomic and proteomic analyses may contribute to develop personalized therapy for cancer patients.

Overcoming multidrug resistance is still challenging, but its comprehensive understanding will bring beneficial therapeutic strategies. In addition to the altered metabolism of cancer cells, exosomes contributing to the tumor microenvironment are worth being investigated for the discovery of biomarkers and for the development of novel drug delivery systems. This Special Issue focuses on the molecular basis of drug resistance in cancer and on MDR reversal agents, with the aim to suggest therapeutic strategies to conquer drug resistance in cancer.

Prof. Dr. Takeo Nakanishi
Prof. Dr. Zhe-Sheng (Jason) Chen
Guest Editors

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Keywords

  • drug resistance
  • TKI inhibitors
  • metabolism
  • apoptosis
  • nanomaterials
  • ABC transporters
  • P-glycoprotein
  • breast cancer resistance protein
  • multidrug resistance protein
  • solute carriers

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Published Papers (4 papers)

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Research

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19 pages, 6723 KiB  
Article
Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death
by Nang Lae Lae Phoo, Pornngarm Dejkriengkraikul, Patompong Khaw-On and Supachai Yodkeeree
Int. J. Mol. Sci. 2021, 22(22), 12512; https://doi.org/10.3390/ijms222212512 - 19 Nov 2021
Cited by 21 | Viewed by 3318
Abstract
Signet ring cell gastric carcinoma (SRCGC) is a lethal malignancy that has developed drug resistance to cisplatin therapies. The aim of this study was to characterize the acquisition of the cisplatin-resistance SRCGC cell line (KATO/DDP cells) and to understand the molecular mechanisms underlying [...] Read more.
Signet ring cell gastric carcinoma (SRCGC) is a lethal malignancy that has developed drug resistance to cisplatin therapies. The aim of this study was to characterize the acquisition of the cisplatin-resistance SRCGC cell line (KATO/DDP cells) and to understand the molecular mechanisms underlying cisplatin resistance. Transcriptomic and bioinformatic analyses were used to identify the candidate gene. This was confirmed by qPCR and Western blot. Aldoketoreductase1C1 and 1C3 (AKR1C1 and AKR1C3) were the most promising molecules in KATO/DDP cells. A specific inhibitor of AKR1C1 (5PBSA) and AKR1C3 (ASP9521) was used to enhance cisplatin-induced KATO/DPP cell death. Although cisplatin alone induced KATO/DDP apoptosis, a combination treatment of cisplatin and the AKR1C inhibitors had no influence on percent cell apoptosis. In conjunction with the autophagy inhibitor, 3MA, attenuated the effects of 5PBSA or ASP9521 to enhance cisplatin-induced cell death. These results indicated that AKR1C1 and 1C3 regulated cisplatin-induced KATO/DDP cell death via autophagy. Moreover, cisplatin in combination with AKR1C inhibitors and N-acetyl cysteine increased KATO/DDP cells’ viability when compared with a combination treatment of cisplatin and the inhibitors. Taken together, our results suggested that AKR1C1 and 1C3 play a crucial role in cisplatin resistance of SRCGC by regulating redox-dependent autophagy. Full article
(This article belongs to the Special Issue Drug Resistance-Associated Proteins in Cancer)
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15 pages, 3153 KiB  
Article
PRP4 Promotes Skin Cancer by Inhibiting Production of Melanin, Blocking Influx of Extracellular Calcium, and Remodeling Cell Actin Cytoskeleton
by Muhammad Bilal Ahmed, Salman Ul Islam and Young Sup Lee
Int. J. Mol. Sci. 2021, 22(13), 6992; https://doi.org/10.3390/ijms22136992 - 29 Jun 2021
Cited by 7 | Viewed by 2855
Abstract
Pre-mRNA processing factor 4B (PRP4) has previously been shown to induce epithelial-mesenchymal transition (EMT) and drug resistance in cancer cell lines. As melanin plays an important photoprotective role in the risk of sun-induced skin cancers, we have investigated whether PRP4 can induce drug [...] Read more.
Pre-mRNA processing factor 4B (PRP4) has previously been shown to induce epithelial-mesenchymal transition (EMT) and drug resistance in cancer cell lines. As melanin plays an important photoprotective role in the risk of sun-induced skin cancers, we have investigated whether PRP4 can induce drug resistance and regulate melanin biosynthesis in a murine melanoma (B16F10) cell line. Cells were incubated with a crucial melanogenesis stimulator, alpha-melanocyte-stimulating hormone, followed by transfection with PRP4. This resulted in the inhibition of the production of melanin via the downregulation of adenylyl cyclase-cyclic adenosine 3′,5′-monophosphate (AC)–(cAMP)–tyrosinase synthesis signaling pathway. Inhibition of melanin production by PRP4 leads to the promotion of carcinogenesis and induced drug resistance in B16F10 cells. Additionally, PRP4 overexpression upregulated the expression of β-arrestin 1 and desensitized the extracellular calcium-sensing receptor (CaSR), which in turn, inhibited the influx of extracellular Ca2+ ions. The decreased influx of Ca2+ was confirmed by a decreased expression level of calmodulin. We have demonstrated that transient receptor potential cation channel subfamily C member 1 was involved in the influx of CaSR-induced Ca2+ via a decreasing level of its expression. Furthermore, PRP4 overexpression downregulated the expression of AC, decreased the synthesis of cAMP, and modulated the actin cytoskeleton by inhibiting the expression of Ras homolog family member A (RhoA). Our investigation suggests that PRP4 inhibits the production of melanin in B16F10 cells, blocks the influx of Ca2+ through desensitization of CaSR, and modulates the actin cytoskeleton through downregulating the AC–cAMP pathway; taken together, these observations collectively lead to the promotion of skin carcinogenesis. Full article
(This article belongs to the Special Issue Drug Resistance-Associated Proteins in Cancer)
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21 pages, 14508 KiB  
Article
The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter
by Silpa Narayanan, Nehaben A. Gujarati, Jing-Quan Wang, Zhuo-Xun Wu, Jagadish Koya, Qingbin Cui, Vijaya L. Korlipara, Charles R. Ashby, Jr. and Zhe-Sheng Chen
Int. J. Mol. Sci. 2021, 22(5), 2463; https://doi.org/10.3390/ijms22052463 - 28 Feb 2021
Cited by 12 | Viewed by 2907
Abstract
The overexpression of ATP-binding cassette transporter, ABCG2, plays an important role in mediating multidrug resistance (MDR) in certain types of cancer cells. ABCG2-mediated MDR can significantly attenuate or abrogate the efficacy of anticancer drugs by increasing their efflux from cancer cells. In this [...] Read more.
The overexpression of ATP-binding cassette transporter, ABCG2, plays an important role in mediating multidrug resistance (MDR) in certain types of cancer cells. ABCG2-mediated MDR can significantly attenuate or abrogate the efficacy of anticancer drugs by increasing their efflux from cancer cells. In this study, we determined the efficacy of the novel benzamide derivative, VKNG-2, to overcome MDR due to the overexpression of the ABCG2 transporter in the colon cancer cell line, S1-M1-80. In vitro, 5 μM of VKNG-2 reversed the resistance of S1-M1-80 cell line to mitoxantrone (70-fold increase in efficacy) or SN-38 (112-fold increase in efficacy). In contrast, in vitro, 5 μM of VKNG-2 did not significantly alter either the expression of ABCG2, AKT, and PI3K p110β protein or the subcellular localization of the ABCG2 protein compared to colon cancer cells incubated with the vehicle. Molecular docking data indicated that VKNG-2 had a high docking score (-10.2 kcal/mol) for the ABCG2 transporter substrate-drug binding site whereas it had a low affinity on ABCB1 and ABCC1 transporters. Finally, VKNG-2 produced a significant concentration-dependent increase in ATPase activity (EC50 = 2.3 µM). In conclusion, our study suggests that in vitro, VKNG-2 reverses the resistance of S1-M1-80, a cancer cell line resistant to mitoxantrone and SN-38, by inhibiting the efflux function of the ABCG2 transporter. Full article
(This article belongs to the Special Issue Drug Resistance-Associated Proteins in Cancer)
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Review

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23 pages, 4105 KiB  
Review
Pleiotropic Roles of ABC Transporters in Breast Cancer
by Ji He, Erika Fortunati, Dong-Xu Liu and Yan Li
Int. J. Mol. Sci. 2021, 22(6), 3199; https://doi.org/10.3390/ijms22063199 - 21 Mar 2021
Cited by 43 | Viewed by 4553
Abstract
Chemotherapeutics are the mainstay treatment for metastatic breast cancers. However, the chemotherapeutic failure caused by multidrug resistance (MDR) remains a pivotal obstacle to effective chemotherapies of breast cancer. Although in vitro evidence suggests that the overexpression of ATP-Binding Cassette (ABC) transporters confers resistance [...] Read more.
Chemotherapeutics are the mainstay treatment for metastatic breast cancers. However, the chemotherapeutic failure caused by multidrug resistance (MDR) remains a pivotal obstacle to effective chemotherapies of breast cancer. Although in vitro evidence suggests that the overexpression of ATP-Binding Cassette (ABC) transporters confers resistance to cytotoxic and molecularly targeted chemotherapies by reducing the intracellular accumulation of active moieties, the clinical trials that target ABCB1 to reverse drug resistance have been disappointing. Nevertheless, studies indicate that ABC transporters may contribute to breast cancer development and metastasis independent of their efflux function. A broader and more clarified understanding of the functions and roles of ABC transporters in breast cancer biology will potentially contribute to stratifying patients for precision regimens and promote the development of novel therapies. Herein, we summarise the current knowledge relating to the mechanisms, functions and regulations of ABC transporters, with a focus on the roles of ABC transporters in breast cancer chemoresistance, progression and metastasis. Full article
(This article belongs to the Special Issue Drug Resistance-Associated Proteins in Cancer)
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