Mitotic spindle defects and DNA damage induced by dimethoxycurcumin lead to an intrinsic apoptosis pathway in...

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Dimethoxycurcumin (DiMC), a synthetic curcumin analog, exhibits antiproliferative effects.
• Hepatocellular carcinoma (HCC) remains a significant global health challenge.
• Understanding DiMC's molecular mechanisms is crucial for therapeutic development.

Purpose of the Study:

• To investigate the cytotoxic, antiproliferative, genotoxic, and apoptotic effects of DiMC.
• To correlate these effects with transcript and protein expression in HepG2/C3A cells.
• To evaluate DiMC's potential as an anticancer therapeutic.

Main Methods:

• Treatment of HepG2/C3A cells with DiMC.
• Analysis of gene and protein expression (CYP enzymes, cell cycle regulators, DNA repair proteins, apoptosis markers).
• Assessment of cytotoxicity, genotoxicity, mitotic arrest, reactive oxygen species generation, and apoptosis.

Main Results:

• DiMC exhibited cytotoxicity at concentrations ≥10 μM and increased CYP2E1, CYP2C19, and CYP1A2 transcript levels.
• DiMC induced mitotic arrest via monopolar spindle formation and was genotoxic, increasing CDKN1A, GADD45A, and PARP1 expression.
• Genotoxicity resulted from reactive oxygen species generation and reduced antioxidant protein levels, alongside decreased DNA repair proteins.
• Apoptosis was induced through the intrinsic pathway, evidenced by morphological changes, annexin labeling, increased BAK1 and CASP7 expression, and caspase 3/7 activity.

Conclusions:

• DiMC effectively induces cell death in hepatocellular carcinoma cells via genotoxicity and apoptosis.
• DiMC modulates key molecular targets involved in cell cycle regulation, DNA repair, and apoptosis.
• DiMC demonstrates considerable potential for anticancer therapy, even in metabolically active cancer models.