Pantoprazole pretreatment elevates sensitivity to vincristine in drug-resistant oral epidermoid carcinoma in vitro and in vivo

• Published in: Biomedicine & pharmacotherapy 2019-12, Vol.120, p.109478-109478, Article 109478
• Main Authors: Lu, Zhen-Ning, Shi, Zhao-Yu, Dang, Yi-Fan, Cheng, Yan-Na, Guan, Yan-Hui, Hao, Zhao-Jun, Tian, Bing, He, Hong-Wei, Guo, Xiu-Li
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Drug Resistance, Neoplasm - drug effects; Female; Humans; KB Cells; Mice; Mice, Inbred BALB C; Mouth Neoplasms - drug therapy; Mouth Neoplasms - metabolism; Multidrug resistance; Oral cancer; Pantoprazole; Pantoprazole - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Proton pump inhibitors (PPIs); Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism; Vincristine; Vincristine - pharmacology
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.109478

Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with oral cancer. Proton pump inhibitors (PPIs), essentially H+-K+-ATPase inhibitors which are currently used in the treatment of acid related diseases, have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to investigate whether pantoprazole (PPZ, one of PPIs) could increase the sensitivity of chemoresistant oral epidermoid carcinoma cells (KB/V) to vincristine (VCR) and elucidate the underlying action mechanism. Results showed that combination treatment of PPZ and VCR synergistically inhibited the proliferation of KB/V cells in vitro and in vivo. Furthermore, administration of PPZ and VCR not only induce apoptosis and G2/M phase arrest in KB/V cells but also suppress the migration and invasion of KB/V cells. The mechanism underlying synergistic anti-tumor effect of PPZ and VCR was related to the inhibition of the function and expression of P-glycoprotein (P-gp) and the down-regulation of EGFR/MAPK and PI3K/Akt/mTOR signaling pathways in KB/V cells. Additionally, we observed that PPZ treatment induced an increase in lysosomal pH and inhibited the activity of lysosomal enzyme acid phosphatase in KB/V cells, which could functionally reduce the sequestration of VCR in lysosomes and sensitized KB/V cells to VCR. In conclusion, our study demonstrated that PPZ could be included in new combined therapy of human oral cancer (especially on VCR-resistant therapy) together with VCR.