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Abstract Title:

Harmines inhibit cancer cell growth through coordinated activation of apoptosis and inhibition of autophagy.

Abstract Source:

Biochem Biophys Res Commun. 2018 03 25 ;498(1):99-104. Epub 2018 Mar 1. PMID: 29501493

Abstract Author(s):

Xinran Geng, Yichang Ren, Fangfang Wang, Danmei Tian, Xinsheng Yao, Youwei Zhang, Jinshan Tang

Article Affiliation:

Xinran Geng

Abstract:

Harmine and its analogs have long been considered as anticancer agents. In vitro analyses suggested that intercalating DNA or inhibiting topoisomerase might contribute to the cytotoxic effect of this class of compound. However, this idea has not been rigorously tested in intact cells. By synthesizing novel derivatives, here we demonstrate that harmines did not activate the DNA damage response, a cellular signaling commonly induced by agents that intercalate DNA or inhibit topoisomerase. These findings suggest that mechanisms other than DNA intercalating or topoisomerase inhibiting contribute to the toxicity of harmines in vivo. Using a novel N-benzyl and N-arylated alkyl compound 10f that has good solubility and stability as the model, we show that harmines strongly inhibited the growth of cancer cells originated from breast, lung, bone and pancreas, but not that of normal fibroblasts. We further show that 10f induced apoptosis and inhibited autophagy in a dose and time-dependent manner. An apoptosis inhibitor suppressed 10f-induced cell death. Together, our results reveal previously unidentified insights into the anticancer mechanism of harmines, supporting future development of this compound class in the treatment of human cancers.

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