Derivatives of 6-cinnamamido-quinoline-4-carboxamide impair lysosome function and induce apoptosis

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Autophagy is a cellular degradation process crucial for cancer cell survival under stress.
• Dysregulation of autophagy is implicated in cancer progression and treatment resistance.

Purpose of the Study:

• To synthesize and evaluate novel 6-cinnamamido-quinoline-4-carboxamide (CiQ) derivatives for their anti-cancer effects.
• To investigate the mechanism of action of CiQ derivatives, focusing on their impact on cancer cell proliferation and autophagy.

Main Methods:

• Synthesis of CiQ derivatives.
• In vitro testing on a broad spectrum of cancer cell lines.
• Assessment of proliferation, apoptosis (caspase-9 activation, PARP cleavage), autophagy markers (ATG5, BECN1, LC3, p62), lysosome membrane permeability (LMP), and extracellular signal-regulated kinase (ERK) pathway activation.

Main Results:

• CiQ derivatives demonstrated broad-spectrum inhibition of cancer cell proliferation.
• CiQ derivatives induced autophagy, leading to impaired autophagic flux, increased LMP, and accumulation of ubiquitinated proteins.
• CiQ-induced cytotoxicity was mediated by apoptosis, and significantly alleviated by blocking autophagy.
• Activation of the ERK pathway by CiQ derivatives was crucial for inducing LMP, altering autophagic flux, and causing cell death.

Conclusions:

• CiQ derivatives are potent anti-cancer agents that inhibit proliferation and induce apoptosis.
• The mechanism involves ERK-mediated disruption of lysosomal function and autophagic flux.
• CiQ derivatives represent a promising class of compounds for cancer therapy, targeting cancer cell survival pathways.