Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment

Sui, Xinbing; Xu, Yi; Wang, Xian; Han, Weidong; Pan, Hongming; Xiao, Mang

doi:10.1021/acs.molpharmaceut.5b00577

Cited by 80 publications

(64 citation statements)

References 104 publications

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“…[61] However, putative molecular targets of metformin are unknown and how this molecule exerts its activity remains mechanistically unclear. [62] Furthermore, MLN0128 has been described to target mTOR and to selectively kill CSCs in AML (acute myeloid leukemia) cells. Finally, epigallocatechin gallate inhibited self-renewal in hepatoma and colon CSCs and attenuated the expression of stem cell markers.…”

Section: Targeting Cscs Through the Hedgehog Signaling Pathwaysmentioning

confidence: 99%

Targeting Cancer Stem Cells with Small Molecules

Müller

Cañeque

Acevedo

et al. 2017

Israel Journal of Chemistry

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Cancers arise as a result of physiological imbalances and subsequent uncontrolled cell division. Cancer initiation requires a set of biochemical alterations, including some occurring at the genetic and epigenetic levels. Thus, tumors are heterogeneous in nature making it challenging to selectively target different cancer cells by means of small molecule intervention. The paradigm of cancer stem cells (CSCs) describes subpopulations of cells with high selfrenewal and tumor-seeding capacity. These cells, typically refractory to conventional therapies, can give rise to relapse after treatment. Combinatorial strategies, including drugs that selectively target this population of cells, have emerged in recent years. Here, we review how discovery-basedunbiased -screening approaches [1] have helped identify small molecules that specifically target CSCs. We also highlight biological pathways characteristic of CSCs that can potentially be selectively targeted in a hypothesis-driven manner by small molecules. We describe molecules that effectively target CSCs and emphasize what is known about their biological modes of action. The diversity and complexity of biochemical processes that CSCs may be addicted to, raises the question of how selective targeting of these pathways can be achieved. This challenge may be addressed by the continuing production of structurally complex and diverse small molecules using target and diversity-oriented synthesis approaches.[2]

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Section: Targeting Cscs Through the Hedgehog Signaling Pathwaysmentioning

confidence: 99%

Targeting Cancer Stem Cells with Small Molecules

Müller

Cañeque

Acevedo

et al. 2017

Israel Journal of Chemistry

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“…Actin was the loading control. Recent studies confirmed the link between the potential application of secondary metabolites as cytotoxic agents and their apoptotic-and autophagic-inducing effects [38,39]. Alkaloids were among these secondary metabolites which exhibited cytotoxic activity against human carcinoma cells through the induction of apoptosis and autophagy [40,41].…”

Section: Isoaaptamine Isolated From Sponge Aaptos Sp Induces Apoptosmentioning

confidence: 94%

Isoaaptamine Induces t-47D Cells Apoptosis and Autophagy via Oxidative Stress

Shih

et al. 2017

65th International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research (GA 2017)

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Abstract:Aaptos is a genus of marine sponge which belongs to Suberitidae and is distributed in tropical and subtropical oceans. Bioactivity-guided fractionation of Aaptos sp. methanolic extract resulted in the isolation of aaptamine, demethyloxyaaptamine, and isoaaptamine. The cytotoxic activity of the isolated compounds was evaluated revealing that isoaaptamine exhibited potent cytotoxic activity against breast cancer T-47D cells. In a concentration-dependent manner, isoaaptamine inhibited the growth of T-47D cells as indicated by short-(MTT) and long-term (colony formation) anti-proliferative assays. The cytotoxic effect of isoaaptamine was mediated through apoptosis as indicated by DNA ladder formation, caspase-7 activation, XIAP inhibition and PARP cleavage. Transmission electron microscopy and flow cytometric analysis using acridine orange dye indicated that isoaaptamine treatment could induce T-47D cells autophagy. Immunoblot assays demonstrated that isoaaptamine treatment significantly activated autophagy marker proteins such as type II LC-3. In addition, isoaaptamine treatment enhanced the activation of DNA damage (γH2AX) and ER stress-related proteins (IRE1 α and BiP). Moreover, the use of isoaaptamine resulted in a significant increase in the generation of reactive oxygen species (ROS) as well as in the disruption of mitochondrial membrane potential (MMP). The pretreatment of T-47D cells with an ROS scavenger, N-acetyl-L-cysteine (NAC), attenuated the apoptosis and MMP disruption induced by isoaaptamine up to 90%, and these effects were mediated by the disruption of nuclear factor erythroid 2-related factor 2 (Nrf 2)/p62 pathway. Taken together, these findings suggested that the cytotoxic effect of isoaaptamine is associated with the induction of apoptosis and autophagy through oxidative stress. Our data indicated that isoaaptamine represents an interesting drug lead in the war against breast cancer.

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“…However, some studies reached conflicting conclusions. Overall, a variety of in vivo and in vitro observations place an emphasis on metformin treatment as a promising therapeutic strategy for cancer prevention and therapy (Sui et al , 2015). Metformin treatment exerts its anticancer role by triggering different processes: it decreases the amount of the Ki67 proliferation marker in biopsy samples of nondiabetic women with breast cancer (DeCensi et al , 2014); it suppresses metastasis formation by preferentially killing stem cells of different cancer types (Hirsch et al , 2009; Vazquez-Martin et al , 2011; Mohammed et al , 2013).…”

Section: Metformin As An Antitumour Drugmentioning

confidence: 99%

The cell-autonomous mechanisms underlying the activity of metformin as an anticancer drug

Sacco¹,

Calderone

Castagnoli

2016

Br J Cancer

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The biguanide drug metformin profoundly affects cell metabolism, causing an impairment of the cell energy balance and triggering a plethora of pleiotropic effects that vary depending on the cellular or environmental context. Interestingly, a decade ago, it was observed that metformin-treated diabetic patients have a significantly lower cancer risk. Although a variety of in vivo and in vitro observations emphasising the role of metformin as anticancer drug have been reported, the underlying mechanisms are still poorly understood. Here, we discuss our current understanding of the molecular mechanisms that are perturbed by metformin treatment and that might be relevant to understand its antitumour activities. We focus on the cell-autonomous mechanisms modulating growth and death of cancer cells.

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Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment

Cited by 80 publications

References 104 publications

Targeting Cancer Stem Cells with Small Molecules

Targeting Cancer Stem Cells with Small Molecules

Isoaaptamine Induces t-47D Cells Apoptosis and Autophagy via Oxidative Stress

The cell-autonomous mechanisms underlying the activity of metformin as an anticancer drug

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