Mitochondrial dysfunction in breast cancer cells prevents tumor growth

Sánchez‐Alvarez, Rosa; Martinez‐Outschoorn, Ubaldo; Lamb, Rebecca; Hulit, James; Howell, Anthony; Gândara, Ricardo; Sartini, Marina; Rubin, Emanuel; Lisanti, Michael P.; Sotgia, Federica

doi:10.4161/cc.23058

Cited by 81 publications

(65 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mitochondrial activity has been shown to be increased in breast cancer metastases Zhao et al, 2013), and agents such as graphene (Zhou et al, 2014) and metformin (Sanchez-Alvarez et al, 2013) have been shown to reduce metastasis via inhibition of the mitochondria. Thus, AG311 could possess antimetastatic activity.…”

Section: Ag311 Induces Necrosis In Breast Cancermentioning

confidence: 99%

A Small Molecule with Anticancer and Antimetastatic Activities Induces Rapid Mitochondrial-Associated Necrosis in Breast Cancer

Bastian

Thorpe

Disch

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Therapy for treatment-resistant breast cancer provides limited options and the response rates are low. Therefore, the development of therapies with alternative chemotherapeutic strategies is necessary. AG311 (5-[(4-methylphenyl)thio]-9H-pyrimido [4,5-b]indole-2,4-diamine), a small molecule, is being investigated in preclinical and mechanistic studies for treatment of resistant breast cancer through necrosis, an alternative cell death mechanism. In vitro, AG311 induces rapid necrosis in numerous cancer cell lines as evidenced by loss of membrane integrity, ATP depletion, HMGB1 (high-mobility group protein B1) translocation, nuclear swelling, and stable membrane blebbing in breast cancer cells. Within minutes, exposure to AG311 also results in mitochondrial depolarization, superoxide production, and increased intracellular calcium levels. Additionally, upregulation of mitochondrial oxidative phosphorylation results in sensitization to AG311. This AG311-induced cell death can be partially prevented by treatment with the mitochondrial calcium uniporter inhibitor, Ru360 [(m)[(HCO 2 )(NH 3 ) 4 Ru] 2 OCl 3 ], or an antioxidant, lipoic acid. Additionally, AG311 does not increase apoptotic markers such as cleavage of poly (ADP-ribose) polymerase (PARP) or caspase-3 and -7 activity. Importantly, in vivo studies in two orthotopic breast cancer mouse models (xenograft and allograft) demonstrate that AG311 retards tumor growth and reduces lung metastases better than clinically used agents and has no gross or histopathological toxicity. Together, these data suggest that AG311 is a first-in-class antitumor and antimetastatic agent inducing necrosis in breast cancer tumors, likely through the mitochondria.

show abstract

Section: Ag311 Induces Necrosis In Breast Cancermentioning

confidence: 99%

A Small Molecule with Anticancer and Antimetastatic Activities Induces Rapid Mitochondrial-Associated Necrosis in Breast Cancer

Bastian

Thorpe

Disch

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…First, the co-cultivation of omental adipose stromal cells (ASC) with endometrial cancer cell line Hec1a stimulates cell proliferation in a greater degree than co-cultivation with subcutaneous fat ASCs (Klopp et al 2012). In addition, the UCP1 hyperexpression by tumor-associated stromal fibroblasts may potentiate cancer growth by providing high-energy nutrients in a paracrine fashion (Sanchez-Alvarez et al 2013). On the other hand, these are certainly not final and only arguments as, for example, there is also data on exactly opposed (antitumor like) influence exerted by UCP1 (Chen et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Features of omental adipose tissue in endometrial cancer patients with ‘standard’ or ‘metabolically healthy’ obesity: associations with tumor process characteristics

et al. 2016

View full text Add to dashboard Cite

PurposeAdipose tissue products may contribute to endometrial cancer (EC) initiation and further growth that encourages the analysis of this issue in patients with different obesity phenotypes.Methods/patientsOmental fat depot characteristics were studied in EC patients (n = 57) with “standard” (SO) or “metabolically healthy” (MHO) obesity. Collected omental samples were evaluated by immunohistochemistry /IHC/ for brown fat marker UCP1, CYP19 (aromatase) and macrophage infiltration markers (CD68, CD163, crown-like structures/CLS) expression. Total RNA extracted from the same samples was investigated for UCP1, CYP19, PTEN and adipokine omentin mRNA.ResultsImmunohistochemistry data revealed a statistically significant increase in aromatase and CD68 expression and tendency to increase of UCP1 expression in SO patients’ omental fat compared to samples obtained from MHO patients. Additionally, positive correlation of EC clinical stage with UCP1 protein and its mRNA content in omental fat was pronounced in MHO as well as SO group, while with omentin mRNA it was discovered only in patients with SO. An inclination to the correlation with better tumor differentiation was seen for UCP1 and CD68 protein expression in patients with MHO and with worse (high grade) differentiation—for CD68 expression in the group with SO.ConclusionsIn aggregate, this suggests that obesity phenotype has significant impact on omental fat tissue characteristics which is related to the clinical course of EC and may have practical consequences.

show abstract

“…This observation might thus indicate that metformin might directly hamper a pivotal aspect of cancer biology and hinder cell energy asset beyond the consequences of mitochondrial impairment 18 , 20 , 21 . Accordingly, we hypothesized that HK I and II inhibition by metformin could modify glucose metabolism in triple-negative breast cancer both in cultured cells and xenograft models.…”

Section: Introductionmentioning

confidence: 99%

Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer

Salani²,

et al. 2013

View full text Add to dashboard Cite

Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of 18F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters. The profound energetic imbalance activates phosphorylation and is subsequently followed by cell death. More importantly, the “in vivo” relevance of this effect is confirmed by studies of orthotopic xenografts of MDA-MB-231 cells in athymic (nu/nu) mice. Administration of high drug doses after tumor development caused an evident tumor necrosis in a time as short as 48 h. On the other hand, 1 mo metformin treatment markedly reduced cancer glucose consumption and growth. Taken together, our results strongly suggest that HK inhibition contributes to metformin therapeutic and preventive potential in breast cancer.

show abstract

Mitochondrial dysfunction in breast cancer cells prevents tumor growth

Cited by 81 publications

References 50 publications

A Small Molecule with Anticancer and Antimetastatic Activities Induces Rapid Mitochondrial-Associated Necrosis in Breast Cancer

A Small Molecule with Anticancer and Antimetastatic Activities Induces Rapid Mitochondrial-Associated Necrosis in Breast Cancer

Features of omental adipose tissue in endometrial cancer patients with ‘standard’ or ‘metabolically healthy’ obesity: associations with tumor process characteristics

Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer

Contact Info

Product

Resources

About