Pharmacological Targeting of Vacuolar H+-ATPase via Subunit V1G Combats Multidrug-Resistant Cancer

Wang, Yuezhou; Zhang, Lei; Wei, Yanling; Huang, Wei; Li, Li; Wu, Anan; Dastur, Anahita; Greninger, Patricia; Bray, Walter M.; Zhang, Chen-Song; Li, Mengqi; Lian, Wenhua; Hu, Zejun; Wang, Xiaoyong; Liu, Gang; Yao, Luming; Guh, Jih‐Hwa; Chen, Lanfen; Wang, Hongrui; Zhou, Dawang; Lin, Sheng-Cai; Xu, Qingyan; Shen, Yuemao; Zhang, Jianming; Jurica, Melissa S.; Benes, Cyril H.; Deng, Xianming

doi:10.1016/j.chembiol.2020.06.011

Cited by 17 publications

(24 citation statements)

References 65 publications

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“…For a more comprehensive perspective of the V‐ATPase inhibitors with anticancer activity, readers can resort to excellent reviews in the field 98,237,265,266 . Recently, nonclassical natural compounds, such as the plant‐derived myrtenal 242 and cleistanthin A or its derivatives, 243,244 the milk‐derived protein lactoferrin, 82,102 the natural cyclodepsipeptide verucopeptin 248 and vitamin D 247 have been tested showing good anticancer activity. Also, the PPIs were found to inhibit V‐ATPase and explored for anticancer therapy 253,254 .…”

Section: Therapeutic Opportunities Based On V‐atpase Activity Modulationmentioning

confidence: 99%

Emerging insights on the role of V‐ATPase in human diseases: Therapeutic challenges and opportunities

Santos-Pereira

Rodrigues

Côrte‐Real

2021

Medicinal Research Reviews

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The control of the intracellular pH is vital for the survival of all organisms. Membrane transporters, both at the plasma and intracellular membranes, are key players in maintaining a finely tuned pH balance between intra‐ and extracellular spaces, and therefore in cellular homeostasis. V‐ATPase is a housekeeping ATP‐driven proton pump highly conserved among prokaryotes and eukaryotes. This proton pump, which exhibits a complex multisubunit structure based on cell type‐specific isoforms, is essential for pH regulation and for a multitude of ubiquitous and specialized functions. Thus, it is not surprising that V‐ATPase aberrant overexpression, mislocalization, and mutations in V‐ATPase subunit‐encoding genes have been associated with several human diseases. However, the ubiquitous expression of this transporter and the high toxicity driven by its off‐target inhibition, renders V‐ATPase‐directed therapies very challenging and increases the need for selective strategies. Here we review emerging evidence linking V‐ATPase and both inherited and acquired human diseases, explore the therapeutic challenges and opportunities envisaged from recent data, and advance future research avenues. We highlight the importance of V‐ATPases with unique subunit isoform molecular signatures and disease‐associated isoforms to design selective V‐ATPase‐directed therapies. We also discuss the rational design of drug development pipelines and cutting‐edge methodological approaches toward V‐ATPase‐centered drug discovery. Diseases like cancer, osteoporosis, and even fungal infections can benefit from V‐ATPase‐directed therapies.

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Section: Therapeutic Opportunities Based On V‐atpase Activity Modulationmentioning

confidence: 99%

Emerging insights on the role of V‐ATPase in human diseases: Therapeutic challenges and opportunities

Santos-Pereira

Rodrigues

Côrte‐Real

2021

Medicinal Research Reviews

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“…V-ATPases are commonly activated in resistant and multidrug-resistant cancer cells (reviewed in reference 47 ). Inhibition of V-ATPase sensitizes tumor cells to anticancer drugs ( 48 , 49 ). V-ATPases are also required for drug resistance in fungi, including S. cerevisiae , C. albicans , and C. glabrata ( 50 , 51 ).…”

Section: Discussionmentioning

confidence: 99%

Multifactorial Mechanisms of Tolerance to Ketoconazole in Candida albicans

Xu¹,

Zhu

et al. 2021

Microbiol Spectr

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“…Meanwhile, recent studies have demonstrated that the acidic cancer microenvironment plays an important role in the drug‐resistance by blocking the uptake of the weakly basic chemotherapeutic drugs and further weakening their effects on cancer cells (Borzi et al, 2019; Guo et al, 2019). Vacuolar H(+)‐ATPase (V‐ATPase) is a specific proton pump of the cells, which pumps protons into the extracellular environment or lumen of membrane‐bound organelles and mainly functions in the control of pHi and pHe (Wang et al, 2020). The expression of V‐ATPase is significantly upregulated in some drug‐resistant cancer cells and can be induced by long‐term chemotherapeutics (Jung et al, 2018; Whitton et al, 2018.…”

Section: Introductionmentioning

confidence: 99%

“…Vacuolar H(+)-ATPase (V-ATPase) is a specific proton pump of the cells, which pumps protons into the extracellular environment or lumen of membrane-bound organelles and mainly functions in the control of pHi and pHe (Wang et al, 2020). The expression of V-ATPase is significantly upregulated in some drug-resistant cancer cells and can be induced by long-term chemotherapeutics (Jung et al, 2018;Whitton et al, 2018.…”

Section: Introductionmentioning

confidence: 99%

Esomeprazole overcomes paclitaxel‐resistance and enhances anticancer effects of paclitaxel by inducing autophagy in A549/Taxol cells

Bai

Ding

et al. 2020

Cell Biology International

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Non‐small‐cell lung cancer (NSCLC) is one of the most common malignancies, and the occurrence of drug‐resistance severely limits the efficacy of anticancer drugs in the treatment of NSCLC. Identification of new agents to reverse drug‐resistance in NSCLC treatment is of great importance and urgency both clinically and scientifically. In the present study, we found that A549/Taxol cells displayed a high level of resistance to paclitaxel with the resistance index up to 231. Importantly, esomeprazole could potentiate the antiproliferative effect of paclitaxel in A549/Taxol cells, but not in A549 cells. Further exploration on the underlying mechanisms revealed that esomeprazole decreased the intracellular pH via inhibiting V‐ATPase expression in A549/Taxol cells. Meanwhile, esomeprazole pretreatment significantly promoted paclitaxel‐induced polymerization of tubulin and enhanced the proportion of G2/M‐arrested cells in A549/Taxol cells. Unfortunately, esomeprazole could only result in a slight decrease in the expression of P‐gp in A549/Taxol cells. Interestingly, esomeprazole significantly increased paclitaxel‐induced apoptosis, which was impeded by the autophagy inhibitor 3‐MA in A549/Taxol cells. Taken together, our data suggest that esomeprazole is a promising chemosensitizer against paclitaxel‐resistant NSCLC by inducing autophagy. Our study also offers a new strategy to solve the paclitaxel‐resistance problem during NSCLC treatment.

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Pharmacological Targeting of Vacuolar H+-ATPase via Subunit V1G Combats Multidrug-Resistant Cancer

Cited by 17 publications

References 65 publications

Emerging insights on the role of V‐ATPase in human diseases: Therapeutic challenges and opportunities

Emerging insights on the role of V‐ATPase in human diseases: Therapeutic challenges and opportunities

Multifactorial Mechanisms of Tolerance to Ketoconazole in Candida albicans

Esomeprazole overcomes paclitaxel‐resistance and enhances anticancer effects of paclitaxel by inducing autophagy in A549/Taxol cells

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