A Novel Synthetic Derivative of Deguelin, SH-174, Exhibits Anti-cancer Activities Against Non-small-cell Lung Cancer Cells

Abstract

The naturally occurring rotenoid, deguelin, has been studied to have a strong anti-cancer efficacy in various types of cancer for more than a decade. However, its intolerable toxicity at therapeutic dose and light-labile physical property deterred its development to be a clinical drug of use. Here, I report that SH-174, a novel synthetic derivative of deguelin, has a strong anti-cancer activity against several non-small-cell lung cancer (NSCLC) cells while having no or a less toxicity to human non-cancerous normal cells (e.g. BEAS-2B, ARPE-19, and HUVEC) than deguelin has. Several NSCLC cell lines were treated with or without SH-174 and subject to MTT assay, colony formation assay, and apoptosis assay

all of which treated with SH-174 exhibited significant inhibited results on the proliferation and survival of those cancer cells. Moreover, SH-174 reduced the ability of cancer cells to adapt to and survive under hypoxic cancer microenvironment by downregulating phosphorylation of Akt and MEK1/2, as well as HIF-1α protein level. To elucidate the target of oncogenic signaling in NSCLC cells by SH-174, I examined the AMPK-mTORC1 signaling axis which is harnessed by cancers for their rapid proliferation and survival. As a result, SH-174 induced the phosphorylation of AMPKα at Thr172, resulting in the inhibition of mTORC1 activity on cellular proliferation. This suggests SH-174 blocks the unchecked proliferation of cancer cells by modulating AMPK-mTORC1 signaling pathway. Thus, SH-174 is a new promising candidate for lung cancer therapy and further in vivo studies in animals are warranted.