期刊
MOLECULAR CANCER THERAPEUTICS
卷 15, 期 12, 页码 2875-2886出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-15-1021
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资金
- Australian Research Council Discovery grant
- Czech Science Foundation [GA15-02203S]
- Czech Ministry of Health grant [AZV 16-31604.A]
- BIOCEV from ERDF [CZ.1.05/1.1.00/02.0109]
- Mitenal from ERDF [CZ.2.16/3.1.00/21531, RVO: 86652036]
- Ministry of Education, Youth and Sports of the Czech Republic at CZ-OPEN-SCREEN: National infrastructure for chemical biology [LO1220]
Pancreatic cancer isone of the hardest-to-treat types of neoplastic diseases. Metformin, a widely prescribed drug against type 2 diabetes mellitus, is being trialed as an agent against pancreatic cancer, although its efficacy is low. With the idea of delivering metformin to its molecular target, the mitochondrial complex I (CI), we tagged the agent with the mitochondrial vector, triphenylphosphonium group. Mitochondrially targeted metformin (MitoMet) was found to kill a panel of pancreatic cancer cells three to four orders of magnitude more efficiently than found for the parental compound. Respiration assessment documented CI as the molecular target for MitoMet, which was corroborated by molecular modeling. MitoMet also efficiently suppressed pancreatic tumors in three mouse models. We propose that the novel mitochondrially targeted agent is clinically highly intriguing, and it has a potential to greatly improve the bleak prospects of patients with pancreatic cancer. (C) 2016 AACR.
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