Cajanol Sensitizes A2780/Taxol Cells to Paclitaxel by Inhibiting the PI3K/Akt/NF-κB Signaling Pathway

Ming Sui,Peiling Li,Mingqi Guo,Jing Jiang,Wenle Li,Zheng Gong,Hairong Yang

doi:10.3389/fphar.2021.783317

Abstract

Ovarian cancer is the second most common gynecological malignancy, and one of the most deadly. The bottleneck restricting the treatment of ovarian cancer is its multi-drug resistance to chemotherapy. Cajanol is an isoflavone from pigeon pea (Cajanus cajan) that has been reported to have anti-tumor activity. In this work, we evaluate the effect of cajanol in reversing paclitaxel resistance of the A2780/Taxol ovarian cancer cell line in vitro and in vivo, and we discuss its mechanism of action. We found that 8 μM cajanol significantly restored the sensitivity of A2780/Taxol cells to paclitaxel, and in vivo experiments demonstrated that the combination of 0.5 mM/kg paclitaxel and 2 mM/kg cajanol significantly inhibited the growth of A2780/Taxol metastatic tumors in mice. Flow cytometry, fluorescence quantitative PCR, western blotting and immunohistochemical staining methods were used to study the mechanism of reversing paclitaxel resistance with cajanol. First, we determined that cajanol inhibits paclitaxel efflux in A2780/Taxol cells by down-regulating permeability glycoprotein (P-gp) expression, and further found that cajanol can inhibit P-gp transcription and translation through the PI3K/Akt/NF-κB pathway. The results of this work are expected to provide a new candidate compound for the development of paclitaxel sensitizers.

Highlights

Ovarian cancer is one of the three major malignant tumors of the female reproductive system and has the highest death rate among all the gynecological malignancies (Deb et al, 2018)
The results showed that cotreatment of cajanol with paclitaxel substantially inhibits A2780/ Taxol cells and that the IC50 value is decreased by more than 4-fold at a cajanol concentration of 8 μM
These results suggest that cajanol effectively reverses the resistance of A2780/Taxol cells to paclitaxel and that the effect is concentration dependent at levels up to 8 μM

Summary

Introduction

Ovarian cancer is one of the three major malignant tumors of the female reproductive system and has the highest death rate among all the gynecological malignancies (Deb et al, 2018). Because ovarian cancer is difficult to diagnose, most ovarian cancer patients are recognized at an advanced stage, leading to a decreased survival rate (Grunewald and Ledermann, 2017). The combination of paclitaxel and platinum chemotherapy is the primary regimen for ovarian cancer patients. At the beginning of the chemotherapy regimen, these drugs are effective for more than 80% of patients, but cancer cells develop resistance to the drugs, which results in cancer recurrence, leading to a five-year survival rate of 45% for ovarian cancer patients. The survival rate of cancer patients diagnosed as terminal is less than 30% (Webb and Jordan, 2017). Studies have shown that drug resistance to paclitaxel involves various mechanisms, including the increase of multi-drug resistance (MDR) proteins (Mihanfar et al, 2019), and alterations in expression of vascular endothelial growth factor (Akiyama et al, 2012), matrix metalloproteinases (Hu et al, 2012; Kato et al, 2012) or microtubule associated proteins

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