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Delta- and Gamma-Tocotrienols Inhibit the Proliferation of HCC2998 Human Colorectal Carcinoma Cells via Modulation of
Ali Qusay Khalid1, Saatheeyavaane Bhuvanendran1, Kasthuri Bai Magalingam1
1Food as Medicine Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Malaysia.
Abstract:
Colorectal cancer (CRC) remains a significant global health burden, necessitating the exploration of novel therapeutic strategies. Tocotrienols (T3s), particularly gamma (γ)- and delta (δ)-T3 isoforms, exhibit promising anticancer properties. This study investigates the antiproliferative effects of γT3 and δT3 on HCC2998 human colorectal carcinoma cells, elucidating their underlying molecular mechanisms through cell viability assays and comprehensive gene expression profiling. The half-maximal inhibitory concentrations (IC₅₀) for γT3 were determined to be 12.59 ± 0.35 µg/mL (24 h), 11.63 ± 0.05 µg/mL (48 h), and 10.92 ± 0.06 µg/mL (72 h). For δT3, the IC₅₀ values were lower: 9.66 ± 0.17 µg/mL (24 h), 9.33 ± 0.00 µg/mL (48 h), and 9.69 ± 0.05 µg/mL (72 h). Microarray analysis revealed that histone modification pathways were most significantly affected, profoundly influencing the DNA damage response (DDR). Specifically, treatment with γT3 and δT3 led to the upregulation of the ATM tumor suppressor gene and downregulation of key DDR-related genes, including BID, BRCA1, CCNE2, CDC25A, CDC25C, CDK2, E2F1, H2AFX, PMAIP1, RAD51, and SMC1A. These findings indicate that γT3 and δT3 inhibit HCC2998 cell proliferation by activating the DDR pathway, highlighting their potential as therapeutic agents to overcome cell cycle arrest resistance in CRC. This study provides critical insights into the molecular actions of γT3 and δT3, supporting their further investigation as promising candidates for CRC intervention.
Insights
Gamma and delta tocotrienols (T3s) show anticancer effects by activating DNA damage response pathways in colorectal cancer cells. These T3 isoforms may offer new therapeutic strategies for colorectal cancer intervention.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Colorectal cancer (CRC) is a major global health concern.
- Novel therapeutic strategies are needed to combat CRC.
- Tocotrienols (T3s), especially gamma (γ)-T3 and delta (δ)-T3, show potential anticancer properties.
Purpose of the Study:
- To investigate the antiproliferative effects of γT3 and δT3 on HCC2998 human colorectal carcinoma cells.
- To elucidate the molecular mechanisms underlying the anticancer effects of γT3 and δT3.
- To explore the potential of γT3 and δT3 as therapeutic agents for CRC.
Main Methods:
- Cell viability assays were performed to determine the half-maximal inhibitory concentrations (IC₅₀) of γT3 and δT3.
- Gene expression profiling using microarray analysis was conducted to identify affected molecular pathways.
- Key genes involved in DNA damage response (DDR) and cell cycle regulation were analyzed.
Main Results:
- γT3 and δT3 demonstrated significant antiproliferative effects on HCC2998 cells, with determined IC₅₀ values.
- Microarray analysis revealed that histone modification pathways were significantly impacted, influencing the DDR.
- Treatment with γT3 and δT3 upregulated the ATM tumor suppressor gene and downregulated several key DDR-related genes (e.g., BID, BRCA1, CCNE2, CDC25A, CDC25C, CDK2, E2F1, H2AFX, PMAIP1, RAD51, SMC1A).
Conclusions:
- γT3 and δT3 inhibit HCC2998 cell proliferation by activating the DNA damage response (DDR) pathway.
- These findings suggest that γT3 and δT3 have the potential to overcome cell cycle arrest resistance in CRC.
- γT3 and δT3 warrant further investigation as promising therapeutic agents for colorectal cancer intervention.
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