Vonoprazan as an adjuvant to cisplatin: enhancing antitumor efficacy while mitigating nephrotoxicity and gastrointestinal adverse effects

Abstract

Background/Objective Cisplatin is a popular platinum-containing chemotherapeutic agent that has been used clinically since the 1970s to manage a wide range of hematologic and solid tumors. However, its therapeutic purpose is restricted by significant dose-related toxicities, particularly nephrotoxicity and gastrointestinal damage. Therefore, the present study assesses the potential protective effects of vonoprazan (a potassium-competitive acid blocker) against cisplatin-provoked organ damage, in addition to examining the impacts of vonoprazan on the antineoplastic activity of cisplatin. Methods Rats were pretreated with vonoprazan (10 or 20 mg/kg) in an in vivo study, and their renal, gastric, and intestinal injuries were assessed using spectrophotometric assays, enzyme-linked immunosorbent assay (ELISA), and immunohistochemical (IHC) analysis. Moreover, the oxidative stress, inflammatory, autophagic, and apoptotic pathways were evaluated. Then, MCF-7 human breast cancer cells were treated with cisplatin alone or in combination with vonoprazan in an in vitro study, and the cell viability, combination index, and apoptosis-related markers were analyzed. Results The in vivo study showed that vonoprazan pre-administration meaningfully lowered the injurious influences of cisplatin on the kidney, stomach, and intestine, as evidenced by improvements in the histopathological changes and decreased levels of serum lactate dehydrogenase (LDH), serum creatinine (sCr), and blood urea nitrogen (BUN). Vonoprazan boosted the antioxidant defenses by increasing the total antioxidant capacity (TAC) and decreasing the malondialdehyde (MDA) levels in the kidney, stomach, and intestinal tissues. Moreover, vonoprazan decreased the early biomarkers of acute kidney injury (KIM-1 and NGAL), improved the gastroprotective mediators (increased cGMP and PGI2; decreased serotonin), and modulated the intestinal epithelial and mucosal injury markers (increased TFF3; decreased IFABP). Vonoprazan also attenuated the inflammasome component (NLRP3) and inflammatory signaling mediators (NF-κB and IL-6) while modulating the autophagy-lysosomal pathway (enhanced LC3 and Beclin-1; decreased p62). However, the in vitro study results revealed that the combination of cisplatin and vonoprazan had a synergistic cytotoxic effect and an enhancing effect on the apoptotic pathway (increased p53 and BAX; decreased BCL2). Conclusion Vonoprazan attenuates cisplatin-induced organ injury while augmenting its anticancer effects; this suggests the potential of vonoprazan as a supportive therapeutic strategy during cisplatin-based chemotherapy.