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

This in vivo cell culture study investigated the effects of harmine (and its derivatives) on cancer cell growth and determined that it inhibits cancerous growth via the coordinated action of two cellular pathways that initiate cell death, without inflicting damage to DNA.

Abstract

“Introduction: 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.

Methods/Results: 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 N²-benzyl and N⁹-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.

Discussion: 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.“

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

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

Introduction

Harmine is a typical natural -carboline alkaloid that shows a broad spectrum of biological activities ranging from anti-viral infection to seizure control to anxiety management and to cell proliferation inhibition. The precise mechanism of action of harmines remains elusive, but it is believed to induce DNA damage and elicit the DNA damage response.

Methods

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