Drug repurposing has become an important strategy for the development of novel anti-cancer drugs. Ciclopirox olamine (CPX), a broad-spectrum fungicide, was recently identified as a potential anticancer agent. However, the molecular mechanisms underlying the anti-cancer effect of CPX are still unclear. The mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation and survival. Dysregulation of mTOR signaling is closely associated tumorigenesis and thus mTOR signaling has become an attractive target for cancer therapy.
Prof. LI Yan’ s group at Kunming Institute of Botany, Chinese Academy of Sciences (KIB/CAS) recently found the new anti-cancer mechanism of CPX, collaborating with Prof. HUANG Shilefrom Louisiana State University Health Sciences Center.
The study showed that CPX inhibited mTOR signaling in a spectrum of human tumor cells. Using rhabdomyosarcoma cells as an experimental model, they found that expression of constitutively active mTOR (E2419K) conferred resistance to CPX inhibition of cell proliferation, suggesting that CPX inhibition of mTORC1 contributed to its anticancer effect.
In line with this, treatment with CPX inhibited tumor growth and concurrently suppressed mTORC1 signaling in RD xenografts. Mechanistically, CPX inhibition of mTORC1 was attributed to activation of AMPK-TSC/raptor pathways. This is supported by the findings that CPX activated AMPK. Inhibition of AMPK with Compound C or ectopic expression of dominant negative AMPKα partially prevented CPX from inhibiting mTORC1. Silencing TSC2 attenuated CPX inhibition of mTORC1, and CPX increased AMPK-mediated phosphorylation of raptor (S792). Therefore, the results indicate that CPX exerts the anticancer effect by activating AMPK, resulting in inhibition of mTORC1 signaling (figure 1).
Figure 1. CPX exerts the anti-cancer effect by activating AMPK, resulting in inhibition of mTORC1 signaling
This study entitled “Ciclopirox olamine inhibits mTORC1 signaling by activation of AMPK” has recently been published online in Biochemical Pharmacology: http://dx.doi.org/10.1016/j.bcp.2016.07.005
This work was supported by the National Natural Science Foundation of China (No. 81302807, H. Zhou), the West Light Foundation of the Chinese Academy of Sciences (H. Zhou), the Joint Funds of the National Natural Science Foundation of China and Yunnan Province (U1402227, Y. Li).
State Key Laboratory of Phytochemistry and Plant Resources in West China
Kunming Institute of Botany, Chinese Academy of Sciences
Prof. LI Yan