A Novel Metabolic Reprogramming Strategy for the Treatment of Diabetes‐Associated Breast Cancer. Issue 6 (12th January 2022)

• Record Type: Journal Article
• Authors: Hao, Qiongyu; Huang, Zhimin; Li, Qun; Liu, Dingxie; Wang, Piwen; Wang, Kun; Li, Jieqing; Cao, Wei; Deng, Wenhong; Wu, Ke; Su, Rui; Liu, Zhongmin; Vadgama, Jay; Wu, Yong
• Is Part Of: Advanced science. Volume 9:Issue 6(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-01-12
• Subjects: breast cancer -- diabetes -- lactate -- MCT4 -- metabolic reprogramming -- metformin; Science -- Periodicals; 505
• DOI: 10.1002/advs.202102303
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Diabetes is directly related to the risk of breast cancer (BC) occurrence and worsened BC prognosis. Currently, there are no specific treatments for diabetes‐associated BC. This paper aims to understand the fundamental mechanisms of diabetes‐induced BC progression and to develop personalized treatments. It reports a metabolic reprogramming strategy (MRS) that pharmaceutical induction of glucose import and glycolysis with metformin and NF‐ κ B inhibitor (NF‐ κ Bi) while blocking the export of excessive lactate via inhibiting monocarboxylate transporter 4 (MCT4) leads to a metabolic crisis within the cancer cells. It demonstrates that the MRS shifts the metabolism of BC cells toward higher production of lactate, blocks lactate secretion, prompts intracellular acidification and induces significant cytotoxicity. Moreover, a novel MCT4 inhibitor CB‐2 has been identified by structure‐based virtual screening. A triple combination of metformin, CB‐2, and trabectedin, a drug that impedes NF‐ κ B signaling, strongly inhibits BC cells. Compared to normal glucose condition, MRS elicits more potent cancer cell‐killing effects under high glucose condition. Animal model studies show that diabetic conditions promote the proliferation and progression of BC xenografts in nude mice and that MRS treatment significantly inhibits HG‐induced BC progression. Therefore, inhibition of MCT4 combined with metformin/NF‐ κ Bi is a promising cancer therapy, especially for diabetes‐associated BC. Abstract : A metabolic reprogramming strategy (MRS) that pharmaceutical induction of glucose import and glycolysis to even higher levels while blocking the export of excessive lactate leads to a metabolic crisis within the cancer cells. MRS can be realized by pharmacological inhibition of MCT4 combined with metformin/NF‐ κ Bi, which is a promising cancer therapy, especially for diabetes‐associated breast cancer.