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Identification and Mechanistic Profiling of Indolin-2-One Derivatives That Induce ROS-Driven Intrinsic Apoptosis in
Rabin Neupane1, Chandrabose Karthikeyan2,3, Saloni Malla1
1Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, Ohio, USA.
Abstract:
A series of 3-(2-oxo-2-arylethylidene)indolin-2-ones were synthesized and evaluated for cytotoxic efficacy in the prostate cancer cell lines (PC-3 and DU145), and the colon cancer cell line (HCT-116), and in noncancerous Madin-Darby canine kidney (MDCK) cells. The majority of the evaluated compounds had cytotoxic efficacy (IC50 < 10 µM) in the prostate and colon cancer cell lines. Compound 3j (Raji 10), with a 4-Me substitution on the phenyl ring, was the most potent in decreasing the proliferation of prostate cancer cells (IC50 < 5 µM; 3.56 ± 0.49 µM in PC-3 and 4.20 ± 0.62 µM in DU145). Similarly, compound 3o (Raji 16), with a 5-Br substitution in the isatin moiety and 4-F substitution in the phenyl ring, had maximal cytotoxic potency in HCT-116 cells (IC50 value of 2.93 ± 0.49 µM). Furthermore, the IC50 value of compounds, Raji 10 and Raji 16 was significantly greater (IC50 > 60 μM) in the MDCK cells, compared to the prostate and colorectal cancer cells (HCT-116). The mechanism of cell death induced by the lead compounds; 3j (Raji 10) and 3o (Raji 16) in PC-3 and HCT-116 cells, respectively, was determined. Compounds Raji 10 and Raji 16 induced apoptotic cell death by activating the intrinsic apoptotic pathway, accompanied by an increase in the levels of reactive oxygen species, induction of nuclear fragmentation, and cell cycle arrest at the G1 phase in HCT-116 cells and S/G2 phase in PC-3 cells. Overall, the in vitro results suggest the potential of these compounds in the management of prostate and colon cancer.
Insights
New anticancer compounds show potent cytotoxic effects against prostate and colon cancer cells. These compounds selectively target cancer cells, inducing apoptosis and offering potential for new cancer therapies.
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.
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