Identification and Mechanistic Profiling of Indolin-2-One Derivatives That Induce ROS-Driven Intrinsic Apoptosis in...

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Pharmacology

Background:

• Prostate and colon cancers are significant global health challenges.
• Development of novel, selective cytotoxic agents is crucial for effective cancer management.
• Indolin-2-one derivatives represent a promising class of compounds for anticancer drug discovery.

Purpose of the Study:

• To synthesize and evaluate novel 3-(2-oxo-2-arylethylidene)indolin-2-one derivatives for cytotoxic activity.
• To assess the selectivity of these compounds against prostate (PC-3, DU145) and colon (HCT-116) cancer cell lines compared to noncancerous (MDCK) cells.
• To elucidate the mechanism of action of the most potent compounds.

Main Methods:

• Synthesis of a series of 3-(2-oxo-2-arylethylidene)indolin-2-one compounds.
• In vitro cytotoxicity assays using prostate (PC-3, DU145), colon (HCT-116), and canine kidney (MDCK) cell lines to determine IC50 values.
• Apoptosis induction studies, reactive oxygen species (ROS) measurement, and cell cycle analysis to investigate the mechanism of cell death.

Main Results:

• Most synthesized compounds exhibited significant cytotoxic efficacy (IC50 < 10 µM) against prostate and colon cancer cell lines.
• Compound 3j (Raji 10) demonstrated potent cytotoxicity in prostate cancer cells (IC50 < 5 µM).
• Compound 3o (Raji 16) showed maximal cytotoxic potency against HCT-116 colon cancer cells (IC50 ≈ 2.93 µM).
• Compounds Raji 10 and Raji 16 displayed significantly lower toxicity in noncancerous MDCK cells (IC50 > 60 µM), indicating selectivity.
• Lead compounds induced apoptotic cell death via the intrinsic pathway, increased ROS levels, nuclear fragmentation, and cell cycle arrest (G1 in HCT-116, S/G2 in PC-3).

Conclusions:

• The synthesized 3-(2-oxo-2-arylethylidene)indolin-2-one derivatives possess significant cytotoxic potential against prostate and colon cancer.
• Compounds Raji 10 and Raji 16 exhibit promising selectivity and induce cancer cell death through apoptosis.
• These findings suggest that these compounds are potential candidates for further development in the management of prostate and colon cancers.