Combined cancer therapy with non-conventional drugs: all roads lead to AMPK.

AMP-activated protein kinase (AMPK) is a key energy sensor that regulates cellular energy homeostasis. AMPK activation is associated with decreased phosphorylation of mammalian target of rapamycin (mTOR) and S6 kinase and causes a general reduction in mRNA translation and protein synthesis. Therefore, AMPK is a novel target for anticancer therapy. Metformin and aspirin are two traditional drugs that are widely used as anti-diabetes and non-steroidal anti-inflammatory drugs (NSAIDs), respectively. Much evidence has confirmed that these two drugs demonstrated encouraging anti-cancer properties. Most importantly, both inhibited tumor proliferation and were mainly dependent on the AMPK/mTOR signaling pathway. In addition, several other drugs, such as resveratrol, berberine, statins, epigallocatechin gallate (EGCG) and capsaicin, have provided a similar capacity for tumor inhibition, and the anti-cancer effects of most of them were mainly the result of AMPK activation. In the current review, we summarize the literature on combination therapy based on these non-classical drugs and their potential mechanisms for activating AMPK. Combinations of these drugs will provide a novel cancer therapeutic regimen.