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Anticancer Study of a Novel Pan-HDAC Inhibitor MPT0G236 in Colorectal Cancer Cells
Feng-Lung Tsai1, Han-Li Huang2,3, Mei-Jung Lai2
1School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Abstract:
Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies and a leading cause of cancer worldwide. Histone deacetylases (HDACs), which regulate cell proliferation and survival, are associated with the development and progression of cancer. Moreover, HDAC inhibitors are promising therapeutic targets, with five HDAC inhibitors approved for cancer treatment to date. However, their safety profile necessitates the exploration of well-tolerated HDAC inhibitors that can be used in cancer therapeutic strategies. In this study, the pan-HDAC inhibitor MPT0G236 reduced the viability and inhibited the proliferation of human colorectal cancer cells, and normal human umbilical vein endothelial cells (HUVECs) showed reduced sensitivity. These findings indicated that MPT0G236 specifically targeted malignant tumor cells. Notably, MPT0G236 significantly inhibited the activities of HDAC1, HDAC2, and HDAC3, Class I HDACs, as well as HDAC6, a Class IIb HDAC, at low nanomolar concentrations. Additionally, it promoted the accumulation of acetyl-α-tubulin and acetyl-histone H3 in HCT-116 and HT-29 cells in a concentration-dependent manner. Furthermore, MPT0G236 treatment induced G2/M cell cycle arrest in CRC cells by initially regulating the levels of cell-cycle-related proteins, such as p-MPM2; specifically reducing p-cdc2 (Y15), cyclin B1, and cdc25C levels; and subsequently inducing apoptosis through the caspase-dependent pathways and PARP activation. Our findings demonstrate that MPT0G236 exhibits significant anticancer activity in human colorectal cancer cells.
Insights
The novel pan-histone deacetylase inhibitor MPT0G236 effectively targets colorectal cancer cells, reducing viability and proliferation. This compound shows promise as a well-tolerated therapeutic agent for colorectal cancer (CRC).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Colorectal cancer (CRC) is a major global health concern.
- Histone deacetylases (HDACs) play a role in cancer development.
- Existing HDAC inhibitors have safety concerns, driving the search for better options.
Purpose of the Study:
- To evaluate the anticancer activity of the pan-HDAC inhibitor MPT0G236 against human colorectal cancer cells.
- To assess the specificity and mechanism of action of MPT0G236.
Main Methods:
- Assessed the effect of MPT0G236 on colorectal cancer cell viability and proliferation.
- Investigated MPT0G236's inhibition of HDAC1, HDAC2, HDAC3, and HDAC6 activity.
- Analyzed MPT0G236's impact on acetylated proteins, cell cycle progression, and apoptosis.
Main Results:
- MPT0G236 selectively reduced viability and proliferation in colorectal cancer cells, sparing normal HUVECs.
- MPT0G236 potently inhibited Class I and Class IIb HDACs, increasing acetylated tubulin and histone H3.
- MPT0G236 induced G2/M cell cycle arrest and apoptosis in colorectal cancer cells via caspase-dependent pathways.
Conclusions:
- MPT0G236 demonstrates significant anticancer activity against human colorectal cancer cells.
- MPT0G236's targeted action and mechanism suggest its potential as a well-tolerated therapeutic agent for CRC.
