Breast Cancer Metabolism and Mitochondrial Activity: The Possibility of Chemoprevention with Metformin

Cazzaniga, Massimiliano; Bonanni, Bernardo

doi:10.1155/2015/972193

Cited by 28 publications

(26 citation statements)

References 87 publications

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“…This modified distinctive source of energy from normal cells is known as the “Warburg effect” [ 4 , 5 ]. Besides enhanced glycolysis, OXPHOS is concomitantly under-operated in most cancer cells [ 6 ]. In addition, during the complexities of cancer development, the sustaining energy requirement under deprivation of nutrient supply stimulates an up-regulation of the de novo lipogenesis (DNL) pathway without depending on the extracellular fatty acid load [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Epistructured catechins, EGCG and EC facilitate apoptosis induction through targeting de novo lipogenesis pathway in HepG2 cells

Khiewkamrop

Phunsomboon

Richert³

et al. 2018

Cancer Cell Int

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BackgroundAbnormally high expression of the mammalian de novo lipogenesis (DNL) pathway in various cancer cells promotes cell over-proliferation and resistance to apoptosis. Inhibition of key enzymes in the DNL pathway, namely, ATP citrate lyase, acetyl-CoA carboxylase, and fatty acid synthase (FASN) can increase apoptosis without cytotoxicity to non-cancerous cells, leading to the search for and presentation of novel selective and powerful targets for cancer therapy. Previous studies reported that epistructured catechins, epigallocatechin gallate (EGCG) and epicatechin (EC) exhibit different mechanisms regarding a strong inducer of apoptosis in various cancer cell lines. Thus, the current study investigated the growth inhibitory effect of EGCG and EC, on the enzyme expression and activity of the DNL pathway, which leads to the prominent activity of carnitine palmitoyl transferase-1 (CPT-1) mediating apoptosis in HepG2 cells.MethodsThe cytotoxicity on HepG2 cells of EGCG and EC was determined by MTT assay. Cell death caused by apoptosis, the dissipation of mitochondrial membrane potential (MMP), and cell cycle arrest were then detected by flow cytometry. We further investigated the decrease of fatty acid levels associated with DNL retardation, followed by evaluation of DNL protein expression. Then, the negative inhibitory effect of depleted fatty acid synthesis on malonyl-CoA synthesis followed by regulating of CPT-1 activity was investigated. Thereafter, we inspected the enhanced reactive oxygen species (ROS) generation, which is recognized as one of the causes of apoptosis in HepG2 cells.ResultsWe found that EGCG and EC decreased cancer cell viability by increasing apoptosis as well as causing cell cycle arrest in HepG2 cells. Apoptosis was associated with MMP dissipation. Herein, EGCG and EC inhibited the expression of FASN enzymes contributing to decreasing fatty acid levels. Notably, this decrease consequently showed a suppressing effect on the CPT-1 activity. We suggest that epistructured catechin-induced apoptosis targets CPT-1 activity suppression mediated through diminishing the DNL pathway in HepG2 cells. In addition, increased ROS production was found after treatment with EGCG and EC, indicating oxidative stress mechanism-induced apoptosis. The strong apoptotic effect of EGCG and EC was specifically absent in primary human hepatocytes.ConclusionOur supportive evidence confirms potential alternative cancer treatments by EGCG and EC that selectively target the DNL pathway.

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Section: Introductionmentioning

confidence: 99%

Epistructured catechins, EGCG and EC facilitate apoptosis induction through targeting de novo lipogenesis pathway in HepG2 cells

Khiewkamrop

Phunsomboon

Richert³

et al. 2018

Cancer Cell Int

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“…Epidemiological studies have previously indicated that metformin may reduce the incidence of cancer in diabetics and improve the outcomes of numerous types of cancer ( 31 – 38 ). Metformin has been revealed to preferentially kill CSCs over non-CSCs in different types of breast tumor, through inhibiting the associated inflammatory response by decreasing the expression of CSC-specific genes ( 39 – 42 ). Metformin was also reported to overcome trastuzumab resistance by specifically killing breast cancer-initiating CD44 + CD24 −/low cells and by inhibiting erb-b2 receptor tyrosine kinase 2/insulin-like growth factor (IGF)-1R receptor interactions ( 43 – 45 ).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Rab27A contributes to metformin-induced suppression of breast cancer stem cells

et al. 2017

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Cancer stem cells (CSCs) are associated with tumor initiation, therapeutic resistance, relapse and metastasis. However, the underlying mechanisms CSCs use to preserve stemness are not yet fully understood. The present study demonstrated that the expression of RAB27A, member RAS oncogene family (Rab27a), which was reported to promote tumor progression by upregulating exocytosis of extracellular vesicles, was higher in mammosphere cells than in adherent MDA-MB-231 breast cancer cells. Downregulation of Rab27A inhibited mammosphere formation by decreasing the proportion of CD44+CD24-/low cells of the MDA-MB-231 cell line. Furthermore, Rab27A overexpression redistributed the cell cycle of breast (b) CSCs. The present study revealed that downregulation of Rab27A enhanced the capacity of metformin, the most widely used oral hypoglycemic drug for the treatment of type II diabetes, to inhibit mammosphere growth. Metformin reduced the expression of Rab27A dose-dependently. These data suggested that Rab27A acts as a mediator of human bCSCs by promoting the growth of mammospheres and that synergistic suppression of Rab27A, alone or in combination with metformin, holds promise for therapeutically targeting bCSCs.

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“…Metformin is a hydrophilic drug whose cellular uptake is dependent on organic cation transporters (e.g., OCT1). Therefore, the cancer heterogeneity of OCT1 expression could affect metformin sensitivity [ 58 ]. In this regard, modifying metformin itself or developing drug carriers might further improve the therapeutic efficiency [ 57 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models

Wang

Zhi

et al. 2017

Oncotarget

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Acquired resistance to chemo-drugs remains a major obstacle to successful cancer therapy. Metformin, a well-documented drug for treating type II diabetes, was recently proposed as a novel agent for tumor treatment. In this study, we found that metformin suppressed MCF7/ADR, a doxorubicin-resistant breast cancer cell line, and acted synergistically with doxorubicin by reversing drug-resistant phenotypes both in vitro and in vivo. Metformin alone dose-dependently inhibited tumor growth, especially the stressful tumor microenvironment of glucose deficiency, and the cytotoxicity of metformin was markedly enhanced by increasing ROS production and ATP depletion. In addition, we found that metformin showed synergistic activity with doxorubicin against MCF7/ADR. Metformin increased nuclear doxorubicin accumulation and overcame drug resistance by down-regulating drug-resistant genes such as P-glycoprotein (Pgp). Metformin alone markedly inhibited MCF7/ADR tumor xenografts and demonstrated synergistic activity with doxorubicin in vivo by eliminating Ki67-positive cancer cells. In addition, metformin suppressed Pgp expression in vivo. In conclusion, our results suggested that metformin could potentially be used in the treatment of chemo-resistant tumors and could restore doxorubicin sensitivity.

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Breast Cancer Metabolism and Mitochondrial Activity: The Possibility of Chemoprevention with Metformin

Cited by 28 publications

References 87 publications

Epistructured catechins, EGCG and EC facilitate apoptosis induction through targeting de novo lipogenesis pathway in HepG2 cells

Epistructured catechins, EGCG and EC facilitate apoptosis induction through targeting de novo lipogenesis pathway in HepG2 cells

Downregulation of Rab27A contributes to metformin-induced suppression of breast cancer stem cells

Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models

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