A Study On The Anti-Tumor And Multi-Drug Resistance Reversing Effects And Their Mechanisms Of AMPK-Targeting Drugs

A study on the anti-tumor and multi-drug resistance reversing effectsand their mechanisms of AMPK-targeting drugsCancer is one of the major malignant diseases detrimental to human health in China and around the world.At present,our clinical traditional method is surgical resection combined with radiotherapy and chemotherapy.However,the traditional method of treatment is limited in practical application due to its high toxicity and side effects,and the poor targeting to the tumor cells.To solve these problems,we need to look for new antitumor drugs with high efficient and low toxicity.,The long-term administration of chemotherapy could cause multi-drug resistance,and it also limits the clinical use of chemotherapy.Our lab tried to find new antitumor drugs with high efficiency and low toxicity,and reversing the multi-drug resistance.Energy metabolism has been a point of penetration for cancer treatment.As the metabolic sensor,AMPK can kill the tumor cells and reverse the drug resistance through regulating the AMPK.Our main results are as followed:(1)As the necessary compound to synthesis the nanomaterials,CTAB showed the selective cytotoxicity on cancer cell line Hep G-2 compared with normal cell line HL-7702.CTAB kills liver cancer cells through inducing cell apoptosis.CTAB activates the p53-Bax pathway via AMPK and then induced the release of cytochrome c from mitochondria to the cytosol.Caspase-9,Caspase-3 and poly(ADP-ribose)polymerase(PARP),which are all well-known downstream molecules of cytochrome c,are also cleaved in a concentration-dependent manner.(2)A new concept is emerging in which reprogramming energy metabolism is one of the hallmarks of cancer drug resistance.Berberine,known as a traditional Chinese medicine with the activity of affecting the so-called energy sensor AMPK,has shown the potential to influence cell energy metabolism in cancer therapy.In this study,we investigated the role of AMPK in breast cancer drug resistance and the effects of different berberine doses on the molecular events controlled by this energy sensor.We observed that different doses of berberine could overcome breast cancer drug resistance in two ways: increasing DOX sensitivity and directly inducing apoptosis.On the one hand,low-dose berberine can enhance DOX sensitivity in drug-resistant breast cancer and inhibit the ATP-dependent drug-efflux pump P-gp through the AMPK-HIF-1?-P-gp pathway.On the other hand,high-dose berberine directly induces apoptosis through the AMPK-p53 pathway without affecting the expression of HIF-1?.Moreover,different doses of berberine-induced AMPK activation enhanced DOX sensitivity and elicited anticancer effects in vivo with low systemic toxicity.Taken together,our results consistently demonstrated that berberine sensitized drug-resistant breast cancer to DOX chemotherapy and directly induced anti-tumour effects through the dose-orchestrated AMPK VIransgeni pathway in vitro and in vivo.Given its high efficiency and low toxicity,berberine appears to be a promising and novel chemosensitizer and chemotherapeutic drug for breast cancer treatment.(3)The hypoxic tumor microenvironment has been considered to be a major cause of the chemoresistance for breast cancer treatment.Berberine,a traditional Chinese medicine with the activity of modulating the energy sensor AMPK,has exhibited efficient and safe property in cancer therapy.Here,we show that different doses of berberine reduced AMPK activation,reversed drug resistance and elicited anticancer effects in hypoxic MCF-7 cells.Meanwhile,berberine significantly inhibited tumor progression in a hypoxic xenograft with reduced systematic toxicity.Our study has demonstrated that low-dose berberine enhanced DOX sensitivity through AMPK-HIF-1?-P-gp pathway,while high-dose berberine directly induced apoptosis by activating AMPK-HIF-1?-p53 pathway in vitro and in vivo.Thus,berberine may be an efficient and safe drug candidate for AMPK targeting,and this study sheds light on a new strategy for the treatment of breast cancer in hypoxia-induced drug resistance.In summary,we use AMPK,which regulates energy metabolism of cells,as an antitumor and reversing drug resistance target,and use CTAB and berberine to kill liver cancer cells and reverse the breast cancer drug resistance,which provides a new theoretical basis for clinical treatment.