Novel application of metformin combined with targeted drugs on anticancer treatment

Abstract

The success of targeted drug therapies for treating cancer patients has attracted broad attention both in the academic community and social society. However, rapidly developed acquired resistance is becoming a newly recognized major challenge to the continuing efficiency of these therapies. Metformin is a well-known natural compound with low toxicity derived from the plant French lilac. Our previous work has highlighted research progress of the combination of clinically applied chemotherapies and metformin by different mechanisms. We have also launched a study to combine metformin with the small molecule targeted drug gefitinib to treat bladder cancer using intravesical administration. Thus, in this minireview, we summarize recent achievements combining metformin with various targeted therapies. This work directs the potential clinical future by selecting available cancer patients and providing precise medicine by the combination of metformin and targeted drugs to overcome resistance and enhance therapeutic efficacies.

Keywords: combination; metformin; small molecular inhibitor; synergistic effect; targeted therapy.

Figure 1

General molecular mechanisms of metformin on inhibiting cancer cell growth. Metformin inhibits mitochondria complex I, activates the adenosine monophosphate activated protein kinase (AMPK) signaling pathway, and/or inhibits the insulin signaling pathway. ACC, acetyl‐coa carboxylase; EMT, epithelial‐mesenchymal transition; IGF‐1, insulin‐like growth factor‐1; IGF‐1R, insulin‐like growth factor‐1 receptor; IR, insulin receptor; OCT1, organic cation transporter 1

Figure 2

Trend of FDA‐approved targeted inhibitors between 1995 and 2017. The number of FDA‐approved targeted antitumor inhibitors increases dramatically, compared with other antitumor drugs

Figure 3

Gefitinib induces tumor cell death and develops resistance. Metformin either targets tumor cells directly or reverses and/or inhibits epithelial‐mesenchymal transition (EMT), differentiation, self‐renewal, and gene mutation/alteration of signaling pathways, which are the consequence of gefitinib‐induced resistance, thus sensitizing the antitumor effect or reducing the drug resistance to gefitinib

Figure 4

Mechanisms of metformin combined with Abs or small molecular inhibitors in cancer treatment. Metformin activates the adenosine monophosphate activated protein kinase (AMPK) pathway, eventually causing inhibition of the mTOR pathway. Metformin also indirectly reduces Akt activation, through insulin‐mediated insulin receptor (IR) and the insulin‐like growth factor‐1 receptor (IGF‐1R)/IR hybrid which activates the PI3/Akt/mTOR and RAS/RAF/MAPK/ERK pathways. These pathways are also inactivated by Abs or small molecule inhibitors. Thus, metformin shows synergy with targeted drugs to reduce protein synthesis and cellular proliferation. EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; IGF‐1, insulin‐like growth factor‐1; IRS, insulin/insulin‐like growth factor‐1 receptor substrate; Shc, Src homology 2/alpha‐collagen related protein; VEGFR, vascular endothelial growth factor receptor