Journal
BIOMOLECULES
Volume 11, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/biom11091373
Keywords
metformin; GPR81; lactate; cancer immunotherapy; PD-1/PD-L1 blockade
Categories
Funding
- National Natural Science Foundation of China [U20A20369, 81822043, 81901687]
- Key Incubation Fund of SYSU [19ykzd29]
- Shenzhen Science and Technology Program [KQTD20190929173853397]
- Pearl River Talent Plan Innovation and Entrepreneurship Team Project of Guangdong Province [2019ZT08Y464]
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This study demonstrates the synergistic effects of lactate/GPR81 blockade and metformin in inhibiting cancer cell growth, as well as enhancing immune cell functions and impacting PD-1 expression. The dual blockade strategy significantly enhances the anti-tumor effects of metformin, potentially leading to tumor regression.
Metformin is a widely used antidiabetic drug for cancer prevention and treatment. However, the overproduction of lactic acid and its inefficiency in cancer therapy limit its application. Here, we demonstrate the synergistic effects of the lactate/GPR81 blockade (3-hydroxy-butyrate, 3-OBA) and metformin on inhibiting cancer cells growth in vitro. Simultaneously, this combination could inhibit glycolysis and OXPHOS metabolism, as well as inhibiting tumor growth and reducing serum lactate levels in tumor-bearing mice. Interestingly, we observed that this combination could enhance the functions of Jurkat cells in vitro and CD8(+) T cells in vivo. In addition, considering that 3-OBA could recover the inhibitory effects of metformin on PD-1 expression, we further determined the dual blockade effects of PD-1/PD-L1 and lactate/GPR81 on the antitumor activity of metformin. Our results suggested that this dual blockade strategy could remarkably enhance the anti-tumor effects of metformin, or even lead to tumor regression. In conclusion, our study has proposed a novel and robust strategy for a future application of metformin in cancer treatment.
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