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

Introduction

Harmine is a natural β-carboline alkaloid with diverse biological activities, including reported anti-proliferative effects against a range of human cancers. Earlier in vitro work had suggested that harmine and related compounds might intercalate DNA or inhibit topoisomerases, and harmine derivatives have been reported to affect multiple cellular enzymes and processes such as cyclin/CDK complexes, MAPK signalling, polo-like kinases, protein synthesis initiation and apoptosis. Despite these suggestions, the precise mechanism by which harmines exert cytotoxicity in intact cells remained unclear, and the activation of the canonical DNA damage response had not been systematically evaluated in cell culture for this compound class. Geng and colleagues set out to clarify the cellular mechanism(s) underlying harmine cytotoxicity. By synthesising several novel N2,9-disubstituted harmine analogues and testing them in multiple cancer cell lines and a normal fibroblast line, the investigators aimed to (1) determine whether harmines activate the DNA damage response (using Chk1 phosphorylation as a readout), (2) identify derivatives with improved anti-cancer activity and selectivity, and (3) define the cellular pathways (apoptosis and autophagy) responsible for growth inhibition. The work focuses on a lead compound designated 10f, chosen for its solubility and stability, to probe dose-, time- and mechanism-dependent effects in vitro.