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Evaluating Cell Death Using Cell-Free Supernatant of Probiotics in Three-Dimensional Spheroid Cultures of Colorectal Cancer Cells
Published on: June 13, 2020
Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer
1Faculty of Pharmacy, Bengbu Medical College, Bengbu, 233000, Anhui, People's Republic of China.
Abstract:
3-Bromopyruvate (3BP) is an energy-depleting drug that inhibits Hexokinase II activity by alkylation during glycolysis, thereby suppressing the production of ATP and inducing cell death. As such, 3BP can potentially serve as an anti-tumorigenic agent. Our previous research showed that 3BP can induce apoptosis via AKT /protein Kinase B signaling in breast cancer cells. Here we found that 3BP can also induce colon cancer cell death by necroptosis and apoptosis at the same time and concentration in the SW480 and HT29 cell lines; in the latter, autophagy was also found to be a mechanism of cell death. In HT29 cells, combined treatment with 3BP and the autophagy inhibitor 3-methyladenine (3-MA) exacerbated cell death, while viability in 3BP-treated cells was enhanced by concomitant treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (z-VAD-fmk) and the necroptosis inhibitor necrostatin (Nec)-1. Moreover, 3BP inhibited tumor growth in a SW480 xenograft mouse model. These results indicate that 3BP can suppress tumor growth and induce cell death by multiple mechanisms at the same time and concentration in different types of colon cancer cell by depleting cellular energy stores.
Insights
3-Bromopyruvate (3BP) depletes cellular energy to induce colon cancer cell death through apoptosis and necroptosis. This energy-depleting drug also inhibited tumor growth in a mouse model, suggesting its anti-tumorigenic potential.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- 3-Bromopyruvate (3BP) is an energy-depleting drug targeting glycolysis.
- Previous studies indicated 3BP induces apoptosis in breast cancer cells via AKT/protein kinase B signaling.
- Understanding 3BP's mechanisms in colon cancer is crucial for its therapeutic potential.
Purpose of the Study:
- To investigate the mechanisms of 3BP-induced cell death in colon cancer cell lines.
- To evaluate the efficacy of 3BP in a colon cancer xenograft mouse model.
Main Methods:
- Treatment of SW480 and HT29 colon cancer cells with 3BP.
- Assessment of cell death mechanisms including apoptosis, necroptosis, and autophagy.
- Combination treatments with specific inhibitors (3-MA, z-VAD-fmk, Nec-1).
- Evaluation of tumor growth in a SW480 xenograft mouse model.
Main Results:
- 3BP induced simultaneous apoptosis and necroptosis in SW480 and HT29 cells.
- Autophagy was identified as an additional cell death mechanism in HT29 cells.
- Inhibition of autophagy exacerbated 3BP-induced cell death, while caspase and necroptosis inhibitors enhanced cell viability.
- 3BP significantly inhibited tumor growth in the SW480 xenograft mouse model.
Conclusions:
- 3BP suppresses colon cancer growth through multiple cell death pathways, including apoptosis and necroptosis.
- The energy-depleting action of 3BP underlies its anti-tumorigenic effects in colon cancer.
- 3BP demonstrates potential as an anti-cancer therapeutic agent for colon cancer.
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