Anticancer Mammalian Target of Rapamycin (mTOR) Signaling Pathway Inhibitors: Current Status, Challenges and Future Prospects in Management of Epilepsy.
The role of phosphatidylinositol 3-kinase linked mammalian target of rapamycin (mTOR) pathway hyperactivation is well established in cancer pathogenesis. Several molecules inhibiting mTOR pathway, leading to inhibition of protein synthesis responsible for angiogenesis of tumor cells have emerged out to be potential anticancers. Similar hyperactivation of mTOR pathway has also reported in epilepsy during latent phase, following precipitating injury causing reorganization of neuronal networks and ultimately leading to induction of seizures. The mTOR inhibitors have also found to attenuate pathological changes in the brain associated with epilepsy, primarily suppression of mossy fiber sprouting. At the same time, a few antiepileptic molecules which have been studied against cancer showed anticancer activity, apart from their principal mechanism of action. These studies suggest mTOR signaling pathway to be a common pathogenic link between cancer and epilepsy. It has been found that, anticancer molecules acting on different molecular targets, that ultimately down regulate the expression of mTOR, can also be used in case of epilepsy to reduce its hyperactivation. There are several unexplored anticancer molecules that act by inhibiting mTOR directly or indirectly available which can be explored as antiepileptic in future. Majority of the molecules which are tested as anticancer do not reach the final phases of clinical trials due to less potency and efficacy, and ultimately a few of them reach the market. Since a lot of experimental/safety studies have already been conducted on such molecules, hence it is worthwhile to test these molecules for other disorders that share common pathogenic pathway like epilepsy, provided their pitfalls have been addressed, as proposed in the present review.
Arindam Ghosh
AG
Mazumder
Yogendra Shantaram
YS
Padwad
Pharmacology and Toxicology Laboratory, CSIR-Institute of Himalayan Bioresource Technology, Palampur- 176061, Himachal Pradesh, India. dsinghpharmacology@gmail.com.
Damanpreet
D
Singh
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000378:metabolism / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D000927:Anticonvulsants; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus