Metformin and statins: a possible role in high-risk prostate cancer

Cadeddu, Giovanna; Hervás-Morón, Asunción; Martín, Marta; Pelari-Mici, Lira; Kirsch, Kathy Ytuza-Charahua de; Hernández-Corrales, Antonio; Vallejo-Ocaña, Carmen; Sastre-Gallego, S.; Carrasco-Esteban, Eliseo; Sancho-García, S.; López-Campos, Fernando

doi:10.1016/j.rpor.2019.12.027

Cited by 4 publications

(3 citation statements)

References 28 publications

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“…Metformin significantly inhibits the sphere-forming ability of breast, pancreatic, and ovarian CSCs, and in combination with chemotherapeutic drugs it markedly reduces the CSC subpopulation and tumor volume [29]. Though metformin has demonstrated an overall benefit in prostate cancer risk [49,50] and a synergic antitumoral effect in combination with other drugs and radiation therapy [51,52], metformin's effect on prostate cancer stem cells remains to be elucidated [53]. On the other hand, it has been shown that AMPK may play a role in morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Sánchez

Vara-Ciruelos

Díaz‐Laviada

2020

Cells

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In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment failure and a poor prognosis. In this study, we demonstrated that long-term androgen signal depletion of prostate LNCaP cells induced a neuroendocrine phenotype followed by re-differentiation towards a “stem-like” state. LNCaP cells incubated for 30 days in charcoal-stripped medium or with the androgen receptor antagonist 2-hydroxyflutamide developed neuroendocrine morphology and increased the expression of the neuroendocrine markers βIII-tubulin and neuron specific enolase (NSE). When cells were incubated for 90 days in androgen-depleted medium, they grew as floating spheres and had enhanced expression of the stem cell markers CD133, ALDH1A1, and the transporter ABCB1A. Additionally, the pluripotent transcription factors Nanog and Oct4 and the angiogenic factor VEGF were up-regulated while the expression of E-cadherin was inhibited. Cell viability revealed that those cells were resistant to docetaxel and 2-hidroxyflutamide. Mechanistically, androgen depletion induced the decrease in AMP-activated kinase (AMPK) expression and activation and stabilization of the hypoxia-inducible factor HIF-1α. Overexpression of AMPK in the stem-like cells decreased the expression of stem markers as well as that of HIF-1α and VEGF while it restored the levels of E-cadherin and PGC-1α. Most importantly, docetaxel sensitivity was restored in stem-like AMPK-transfected cells. Our model provides a new regulatory mechanism of prostate cancer plasticity through AMPK that is worth exploring.

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Section: Discussionmentioning

confidence: 99%

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Sánchez

Vara-Ciruelos

Díaz‐Laviada

2020

Cells

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“…However, several studies also revealed that Complex I activity was extremely high when the metformin dose was in the range of 20-80 mmol/L [68,69]; thus, the dose-and time-dependent manner of metformin may modulate the extent of Complex I activation. In fact, other studies showed that high-dose metformin exerts a direct anticancer effect, which requires adequate metformin accumulation in neoplastic tissue to inhibit mTOR and fatty acid synthesis via APMK activation and induce cellular energetic stress and energetic crisis, leading to tumor cell death [70,71]. Zakikhani et al revealed that treatment with 5~20 mM metformin more effectively reduced cell proliferation of breast (MCF-7), ovary (SKOV3 and OVACR-3), and prostate (PC-3) cancer cells through up-regulation of AMPK and down-regulation of mTOR and p70S6K [40].…”

Section: Discussionmentioning

confidence: 99%

Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo

Chen

Yang

et al. 2021

Cancers

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Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.

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“…[131][132][133] However others found no significant difference with metformin use. 134,135 In contrast, seven studies of metformin use amongst men treated with radical prostatectomy all found no association with risk of biochemical relapse. [136][137][138][139][140][141][142] A meta-analysis of eight studies with all treatment types found that metformin use was associated with improved recurrence free survival in men with localized PCa (HR 0.60, 95% CI 0.42-0.87).…”

Section: Therapeutic Advances Inmentioning

confidence: 97%

Targeting lipid metabolism in metastatic prostate cancer

et al. 2023

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Despite key advances in the treatment of prostate cancer (PCa), a proportion of men have de novo resistance, and all will develop resistance to current therapeutics over time. Aberrant lipid metabolism has long been associated with prostate carcinogenesis and progression, but more recently there has been an explosion of preclinical and clinical data which is informing new clinical trials. This review explores the epidemiological links between obesity and metabolic syndrome and PCa, the evidence for altered circulating lipids in PCa and their potential role as biomarkers, as well as novel therapeutic strategies for targeting lipids in men with PCa, including therapies widely used in cardiovascular disease such as statins, metformin and lifestyle modification, as well as novel targeted agents such as sphingosine kinase inhibitors, DES1 inhibitors and agents targeting FASN and beta oxidation.

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Metformin and statins: a possible role in high-risk prostate cancer

Cited by 4 publications

References 28 publications

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo

Targeting lipid metabolism in metastatic prostate cancer

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