Acidic pH at physiological salinity enhances the antitumor efficacy of lenvatinib, a drug targeting vascular endothelial growth factor receptors

Anti-angiogenic therapies have several clinical benefits for patients with tumors.The acidic environment of tumor cells degrades the extracellular matrix, releases several growth factors, such as vascular endothelial growth factor (VEGF), and induces angiogenesis.By contrast, a high-salt diet induces osmotic stress and salt-sensitive hypertension in patients treated with anti-angiogenic drugs.However, the consequences of various salinity conditions in combination with the pH of the tumor microenvironment have not yet been characterized, at least to the best of our knowledge, and are thus the focus of the present study.Herein, molecular dynamics simulations were performed between lenvatinib and VEGF receptor 2 (VEGFR2) at two different pH levels (acidic pH, 6.5; basic pH, 7.5) and three different salinity conditions (0.15, 030 and 0.45 M).The results suggested that, compared with the basic pH, the acidic pH reduced the binding affinity of lenvatinib to VEGFR2 and induced tumor cell viability by enhancing the expression of cyclin-dependent kinase 2 (CDK2), fatty acid synthase (FASN), DnaJ heat shock protein family (Hsp40) member C9 (DNAJC9), c-JUN, Bcl-xL and dual specificity phosphatase 6 (DUSP6).It was also observed that physiological salinity (0.15 M) reversed the tumorigenic effect of the acidic pH by enhancing the binding affinity of lenvatinib, decreasing cell viability and migration, inhibiting the expression of CDK2, FASN, DNAJC9, c-JUN, Bcl-XL, BAX and DUSP6, and increasing the expression of VEGFR2 in MDA-MB-231 breast cancer cells.However, opposite results were obtained under the same salinity conditions at a basic pH.These results suggest that physiological salinity conditions at an acidic pH enhance the antitumor efficacy of antiangiogenic drugs targeting VEGFR2.Overall, the present study suggests that the salinity and pH of the tumor environment play a crucial role in the antitumor efficacy of therapies targeting VEGFR2-mediated angiogenesis.