Combination of metformin with chemotherapeutic drugs via different molecular mechanisms.
Metformin, a widely prescribed drug for treating type II diabetes, is one of the most extensively recognized metabolic modulators which has shown an important anti-cancer property. However, fairly amount of clinical trials on its single administration have not demonstrated a convincing efficiency yet. Thus, recent studies tend to combine metformin with clinical commonly used chemotherapeutic drugs to decrease their toxicity and attenuate their tumor resistance. These strategies have displayed promising clinical benefits. Interestingly, metformin experiences a diversity of molecular mechanisms when it combines different chemotherapeutic drugs. For example, AMPK/mTOR signaling pathway activation plays a major role when it combines with hormone modulating drugs. In contrast, suppression of HIF-1, p-gp and MRP1 protein expression is its main mechanism when metformin combines with anti-metabolites. Furthermore, when combining of metformin with antibiotics, inhibition of oxidative stress and inflammatory signaling pathway becomes a novel pharmaceutical mechanism for its cardio-protective effect. Induction of apoptotic mitochondria and nucleus could be the major player for the synergistic effect of its combination with cisplatin. In contrast, down-regulation of lipoprotein or cholesterol synthesis might be the undefined molecular base when metformin combines with taxane. Thus, deep exploration of molecular mechanisms of metformin with these different drugs is critical to understand its synergistic effect and help for personalized administration. In this mini-review, detailed molecular mechanisms of these combinations are discussed and summarized. This work will promote better understanding of molecular mechanisms of metformin and provide precise targets to identify specific patient groups to achieve satisfactory treatment efficacy.
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, China; Animal Nutrition and Human Health Laboratory, Hunan Normal University, Changsha, Hunan 410013, China. Electronic address: pmaichixj@163.com.
Mei
M
Peng
Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, China; Animal Nutrition and Human Health Laboratory, Hunan Normal University, Changsha, Hunan 410013, China.
Kwame Oteng
KO
Darko
Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, China; Animal Nutrition and Human Health Laboratory, Hunan Normal University, Changsha, Hunan 410013, China.
Ting
T
Tao
Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, China; Animal Nutrition and Human Health Laboratory, Hunan Normal University, Changsha, Hunan 410013, China.
Yanjun
Y
Huang
Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, China; Animal Nutrition and Human Health Laboratory, Hunan Normal University, Changsha, Hunan 410013, China.
Qiongli
Q
Su
Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, China; Animal Nutrition and Human Health Laboratory, Hunan Normal University, Changsha, Hunan 410013, China.
Caimei
C
He
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Tao
T
Yin
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Zhaoqian
Z
Liu
Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, China; Animal Nutrition and Human Health Laboratory, Hunan Normal University, Changsha, Hunan 410013, China. Electronic address: Xiaoping.Yang@hunnu.edu.cn.
Xiaoping
X
Yang
D000726:Androgen Antagonists / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008727:Methotrexate / Q000008:administration & dosage; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage; D050257:Tubulin Modulators / Q000627:therapeutic use; D000093542:Gemcitabine
D000726:Androgen Antagonists; D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D020847:Estrogen Receptor Modulators; D050257:Tubulin Modulators; D003841:Deoxycytidine; D003520:Cyclophosphamide; D008687:Metformin; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil; D008727:Methotrexate; D000093542:Gemcitabine
Chemotherapeutic drugs; Combination; Mechanisms; Metformin