Differential Induction of Cytoplasmic Vacuolization and Methuosis by Novel 2-Indolyl-Substituted Pyridinylpropenones

Abstract

Because many cancers harbor mutations that confer resistance to apoptosis, there is a need for therapeutic agents that can trigger alternative forms of cell death. Methuosis is a novel form of non-apoptotic cell death characterized by accumulation of vacuoles derived from macropinosomes and endosomes. Previous studies identified an indole-based chalcone, 3-(5-methoxy-2-methylindol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (MOMIPP), that induces methuosis in human cancer cells. Herein, we describe the synthesis of related 2-indolyl substituted pyridinylpropenones and their effects on U251 glioblastoma cells. Increasing the size of the 2-indolyl substituent substantially reduces growth inhibitory activity and cytotoxicity, but does not prevent cell vacuolization. Computational models suggest that the results are not due to steric-driven conformational effects. The unexpected uncoupling of vacuolization and cell death implies that the relationship between endosomal perturbations and methuotic cell death is more complex than previously realized. The new series of compounds will be useful in further defining the molecular and cellular mechanisms underlying methuosis.

Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity

“…Accumulation of vacuoles ultimately displaces the cytoplasm and the cell membrane loses integrity and ruptures. While dysfunctional vesicular trafficking and accumulation of vacuoles appear to contribute to cell death, there is evidence that additional metabolic or cellular insults are required for execution of the methuosis cell death program [8,10,11]. …”

“…An initial search for compounds reported to induce cellular vacuolization led us to an indolyl-pyridinyl-propenone (IPP, also referred to as indole-derived chalcone) as a potential lead [13]. Associated structure-activity relationship (SAR) studies revealed that the optimized scaffold for induction of methuosis consists of a 2,5-disubstituted indole and a pyridine in the para -configuration, bridged by an α,β-unsaturated ketone [11,14,15]. Our previously reported IPP compounds, and their modes of biological activity, are summarized in Fig.…”

“…For instance, analogues with larger aliphatic substitutions ( 2e–2g ) on the 2-indolyl position caused vacuolization but had surprisingly less cytotoxicity than the vacuole-inducing compounds with Me ( 1a ) or Et ( 1b ) at this position (Fig. 1) [11]. Similarly, certain 5-substituted analogues ( 2a–2c ), as well as the 2-des-methyl derivative 2d , also induced vacuole formation but were not cytotoxic [15].…”

Catastrophic vacuolization

“…[5][6][7][8] The nonapoptotic cell death pathway described in those papers "appears similar if not identical to what is described by the Karolinska team, " noted Roth.…”

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

“…Similar improvements in activity have been reported due to inclusion of a 5-methoxy group on an indole scaffold elsewhere. [68][69][70] The same group has recently published a paper on the synthesis and activity of a series of MOMIPP analogues, [71] which shows that increasing the size of the aliphatic substituent at the 2-position does not reduce vacuolisation but does reduce the cytotoxicity of the compounds. Work on this form of cell death via the use of indoles is still ongoing by this group.…”