Proton pump inhibitors interfere with the anti-tumor potency of RC48ADC

• Published in: Toxicology in vitro Vol. 79; p. 105292
• Main Authors: Zhang, Xinling, Wang, Yue, Luo, Wenting, Zhu, Marie M., Huang, Changjiang
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2022; Elsevier Science Ltd
• Subjects: Adenosine triphosphatase; Antagonists; Antibodies; Antibodies, Monoclonal, Humanized - pharmacology; Anticancer properties; Antineoplastic Agents, Immunological - pharmacology; Antitumor agents; Cancer; Cathepsin B; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cholecystokinin; Cimetidine; Cimetidine - pharmacology; Drug dosages; Drug interaction; Drug Interactions; ErbB-2 protein; Gastric juice; H+-transporting ATPase; Humans; Hydrogen; Immunoconjugates - pharmacology; Inhibitors; Omeprazole; Proton pump inhibitors; Proton Pump Inhibitors - pharmacology; Proton-Translocating ATPases - drug effects; Protons; RC48ADC; Tumors; Vacuolar H+-ATPase; MMAE; RC48ADC; Cmax; V-ATPase; Cimetidine; ADCs; PPIs; mAb; Cat-B; Cathepsin B; Proton pump inhibitors; Vacuolar H+-ATPase; HER2; Vacuolar H(+)-ATPase
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2021.105292

Antibody-drug conjugates (ADCs) are a promising modality for cancers, but the interaction between them and proton pump inhibitors (PPIs), the common adjuvant drugs for cancer treatment, has not been understood. Here, the interactions between PPIs and RC48ADC, a novel HER2-targeting ADC, were quantified in vitro. CCK-8 assay showed that RC48ADC displayed a significant inhibitory effect on the proliferation of SK-BR-3, NCI-N87 and SK-OV-3 cells with the IC50 values of 4.91 ± 1.15 ng/mL, 14.54 ± 0.85 ng/mL and 11.28 ± 0.68 ng/mL respectively. PPIs alone had no significant anti-tumor effect in the dose range of 1.37–1000 ng/mL. When used together, PPIs inhibited the anti-tumor activity of RC48ADC in a dose-dependent manner. And 1000 ng/mL (~Cmax) PPIs significantly recovered RC48ADC-inhibited cell proliferation by (32.85 ± 2.81) % (p < 0.05). However, cimetidine, a non-PPIs gastric acid secretion inhibitor, had no significant inhibitory effect on RC48ADC. Furthermore, omeprazole, rather than cimetidine, significantly reduced the activity of vacuolar H+-ATPase and Cathepsin B compared with the control cells. These results, if confirmed in vivo, indicate that PPIs are antagonists of RC48ADC, even all ADCs, appearing to be due to inhibition of vacuolar H+-ATPase activity. Moreover, cimetidine combined with ADCs instead of PPIs can prevent an adverse drug interaction. •Approximately 20% of cancer patients are treated with PPIs.•PPIs affect the side effect and efficacy of chemotherapeutic drugs via V-ATPase.•V-ATPase maintains the acid environment of lysosome (pH 4.5–5).•Lysosome is the key site for ADCs to achieve anti-tumor action.•PPIs inhibited ADCs activity via inhibiting V-ATPase activity.