Pantoprazole pretreatment elevates sensitivity to vincristine in drug-resistant oral epidermoid carcinoma in vitro and in vivo
Autor: | Zhao-Yu Shi, Bing Tian, Xiu-Li Guo, Zhao-Jun Hao, Zhen-ning Lu, Yan-Na Cheng, Yanhui Guan, Yi-Fan Dang, Hong-Wei He |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
MAPK/ERK pathway Vincristine Proton pump inhibitors (PPIs) Cell Survival Antineoplastic Agents Apoptosis RM1-950 Multidrug resistance KB Cells Cell Line Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Pantoprazole Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Pharmacology Mice Inbred BALB C Chemistry Oral cancer TOR Serine-Threonine Kinases General Medicine In vitro 030104 developmental biology Epidermoid carcinoma Drug Resistance Neoplasm 030220 oncology & carcinogenesis Carcinoma Squamous Cell Cancer research Female Mouth Neoplasms Therapeutics. Pharmacology Signal Transduction medicine.drug |
Zdroj: | Biomedicine & Pharmacotherapy, Vol 120, Iss, Pp-(2019) |
ISSN: | 0753-3322 |
Popis: | 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. |
Databáze: | OpenAIRE |
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