Abstract
Metabolic reprogramming is thought to be one of the initiators in cancer drug resistance. It has been shown that CTAB is capable of interfering the efficiency of cancer therapy by regulation of cell metabolic reprogramming. In this study, we hypothesized that AMPK as a key metabolic regulator plays a crucial role in regulation of breast cancer drug resistance, which could be alleviated by treatment of CTAB. We observed that CTAB can improve the DOX sensitivity of the breast cancer cells by inhibition of the ATP-dependent drug-efflux pump P-gp complex through activation of the AMPK-HIF-1α-P-gp cascades. The CTAB effect was also confirmed in vivo showing low systemic toxicity. Taken together, our results showed that CTAB sensitized drug resistance of breast cancer to DOX chemotherapy by activating AMPK signaling cascades both in vitro and in vivo, suggested that CTAB may be developed as a promising and novel chemosensitizer and chemotherapeutic candidate for breast cancer treatment.
Highlights
Breast cancer is one of the lethal malignancy in female and has a relative lower survival rate in women (Dey et al, 2019)
We found that CTAB enhanced DOX chemosensitivity of breast cancer mainly through activation of AMPK signaling cascades
The MTT results showed that DOX at an initial dose of 0.36 μg/ml inhibited significantly cell proliferation of MCF-7, while DOX did not have any effect on cell proliferation of MCF-7/ multiple drug resistance (MDR) until it was at an effective dose of 2.5 μg/ml (Figure 1A)
Summary
Breast cancer is one of the lethal malignancy in female and has a relative lower survival rate in women (Dey et al, 2019). The exact molecular mechanisms underlying DOXmediated drug resistance of breast cancer are still poorly defined. Understanding better the pathogenesis of therapeutic resistance is of great importance to develop novel therapeutic strategies to improve the prognosis of breast cancer patients. Cellular metabolic reprogramming event may be closely related to cancer drug resistance (Bhattacharya et al, 2016). Due to cellular metabolic rewiring and reprogramming, the metabolic characteristics (i.e., metabolic phenotypes) were altered, resulting in the changed microenvironment of cancer cells facilitating cancer cells’ apoptotic escape during chemotherapy and radiotherapy (Icard et al, 2018). One of the most prominent mechanisms underlying multiple drug resistance (MDR), for example, is characterized as an over-expression of ATP binding cassette
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