The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer.

Abstract

Background: Oxaliplatin (OXA) is among the most common chemotherapy drugs and is the base component of the FOLFOX regimen (OXA + leucovorin + 5-fluorouracil) and CapeOX regimen (OXA + capecitabine). Resistance to and failure of these two OXA-based regimens often results in poor outcomes in patients with colorectal cancer (CRC). Nitrendipine (NTD) is a first-line antihypertensive drug commonly used in hypertension and coronary heart disease with confirmed low toxicity and side effects. However, the potential benefits of NTD for CRC progression and therapy remain unclear.

Methods: Cell counting kit-8 (CCK-8) detection, colony formation assay, wound-healing assay, Transwell assay, SynergyFinder webtool, and subcutaneous tumor models were used to assess the effect of NTD with OXA on CRC inhibition in vitro and in vivo. Bioinformatics tools including Human Protein Atlas (HPA), quantitative real-time polymerase chain reaction, western blotting analyses, lentivirus transfection, and rescue experiment were used to investigate the mechanism(s) of the related action.

Results: Utilizing murine and human CRC cell lines, the in vitro and in vivo experiment demonstrated that NTD inhibited cell proliferation, migration, and invasion, and the synergy scores calculated by SynergyFinder indicated that NTD exhibited synergistic activity with the chemotherapeutic drug OXA. The CCK-8 detection, animal model, and rescue experiment results demonstrated that NTD suppressed CRC progression and potentiated OXA therapeutic effect by downregulating calcium voltage-gated channel subunit alpha1 D (CACNA1D).

Conclusions: This study presents novel data on first-line antihypertensive NTD, exerting inhibitory effects on cell proliferation and migration in CRC and revealing synergistic activity with OXA by downregulating CACNA1D. NTD may be a candidate as a promising chemosensitizer as an OXA new combination to improve the efficacy and safety of CRC therapy.