Anticancer Activity of Metformin: A Systematic Review of the Literature

Figures & data

Figure 1. Flow of the information searched through the current systematic review.

The different stages of search for the current systematic review. The initial search yielded 96 articles based on their titles, but the majority were excluded after reviewing the abstract. The remainder were screened and only 12 articles were included in the review.

Table 1. List of studies included in the review.

No	Study	Title	Year	Study design	Outcome	Ref.
1	Zakikhani et al.	Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells	2006	Used insulin sensitive breast cancer cells	Metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells	[17]
2	Deng et al.	Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers	2012	The effect of metformin was tested in four different human breast cancer cell lines	Metformin inhibits Stat3 activation (P-Stat3) at Tyr705 and Ser727 and downstream signaling	[18]
3	Liu et al.	Activation of AMPK by metformin promotes renal cancer cell proliferation under glucose deprivation through its interaction with PKM2	2019	The action and mechanism of metformin were confirmed in two renal cancer cell lines and BALB/C nude mice	Antiproliferative effects of metformin in cancer cells are highly dependent on the glucose concentration in the extracellular environment	[19]
4	Ma et al.	Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways	2019	The activity of metformin was confirmed using three ovarian cancer cell lines and in mouse xenograft model	Metformin induces ER stress and cell apoptosis, and ASK1 plays an important role in the antitumor effect of metformin in vivo	[20]
5	Hart et al.	SPHK1 is a novel target of metformin in ovarian cancer	2019	The activity was confirmed using human serum samples, ovarian cancer cell lines and nude mice model	Anticancer activity of metformin may be via the regulation of SPHK1 and S1P expression	[21]
6	Wang et al.	Metformin induces human oesophageal carcinoma cell pyroptosis by targeting the miR-497/PELP1 axis	2019	The mechanism of action was determined using human oesophageal carcinoma cells and immunodeficient mice	Mechanistically, metformin induces pyroptosis of ESCC by targeting miR-497/PELP1 axis	[22]
7	Lu et al.	Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling	2019	The study was performed in vitro using human AGS gastric adenocarcinoma cell line	Metformin induces apoptosis may involve ERK, JNK and p38 MAPK-regulated pathways in AGS cells	[23]
8	Tseng et al.	Metformin treatment suppresses melanoma cell growth and motility through modulation of microRNA expression	2019	The mechanism of action was determined in two different human melanoma cell lines	Metformin treatment suppressed the motility and growth of melanoma cells due to direct modulation of miR-192-5p-EFEMP1 and miR-584-3p-SCAMP3 axes in melanoma cells	[24]
9	Hanawa et al.	Antitumor effects of metformin via indirect inhibition of protein phosphatase 2A in patients with endometrial cancer	2018	Human data followed by confirmation of mechanism of action using two endometrial cancer cell lines HEC265 and HEC1B	Metformin reduced the expression of PP2A in patients with EC and that the reduction of PP2A expression was related to the antiproliferative effect of metformin	[25]
10	Wu et al.	An Ancient, unified mechanism for metformin growth inhibition in Caenorhabditis elegans and cancer	2016	The results were obtained using Hela Cells and C. elegans	Anticancer activity of metformin is attributable to its inhibition of mitochondrial complex I	[26]
11	Zordoky et al.	The antiproliferative effect of metformin in triple-negative MDA-MB-231 breast cancer cells is highly dependent on glucose concentration: implications for cancer therapy and prevention	2014	The results were obtained using triple-negative MDA-MB-231 breast cancer cells	The antiproliferative effect of metformin thought to be achieved through an AMPK-dependent mechanism	[27]
12	Chen et al.	Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer	2017	This is an in vivo study using genetically modified mice model (oncogenic Kras-mediated PDAC) mouse models	The anti-angiogenic effects of metformin is confirmed and that the mechanism is likely through AMPK and or STAT3	[28]

EC: Endometrial cancer; ER: Endoplasmic reticulum; ESCC: Esophageal squamous cell carcinoma; PDAC: Pancreatic ductal adenocarcinoma.

Figure 2. Potential antiproliferative mechanisms of metformin.

Metformin’s potential activation of the apoptotic pathway. It is thought that metformin inhibits tumor growth and progression via activation of apoptosis. For instance, it was claimed that metformin enhances apoptosis by targeting AMPK and AKT/mTOR pathways. It was also reported that metformin activates Stat3 through an mTOR independent manner as well as via an AMPK/mTOR dependent way.

Figure 3. The effect of glucose environment on metformin’s antiproliferative activity.

The effect of glucose levels of low/normal on the antiproliferative activity of metformin. Some reports have suggested that glucose starvation increases ROS production that triggers ER stress induced apoptosis through ROS/ASK1/JNK pathway or via Bcl-2 signaling, which is thought to enhance metformin’s antiproliferative activity. To the contrary, others reported that low glucose may hinder metformin’s antiproliferative activity and that treatment with metformin significantly reduced the expression level of the proliferation marker Ki-67 in normal glucose, but the opposite was observed with in glucose environment.

ER: Endoplasmic reticulum; ROS: Reactive oxygen species.

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