Chemosensitizing effects of metformin on cisplatin- and paclitaxel-resistant ovarian cancer cell lines

Guimarães, Isabella dos Santos; Ladislau-Magescky, Taciane; Tessarollo, Nayara G.; Santos, Diandra Zipinotti dos; Gimba, Etel Rodrigues Pereira; Sternberg, Cinthya; Silva, Ian Victor; Rangel, Letícia Batista Azevedo

doi:10.1016/j.pharep.2017.11.007

Cited by 43 publications

(26 citation statements)

References 29 publications

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“…This major cytotoxicity was due to a synergic effect of Metf and MAL-PDT and not to an additive effect. Our results are in agreement with other studies and indicate that Metf improves the cytotoxicity induced by PDT with 5-aminolevulinc acid in human oral squamous cell carcinoma [41] or by chemotherapy using paclitaxel or cisplatin in other cell lines [42,43].…”

Section: Discussionsupporting

confidence: 93%

Metformin as an Adjuvant to Photodynamic Therapy in Resistant Basal Cell Carcinoma Cells

Mascaraque

Delgado-Wicke

Nuevo‐Tapioles

et al. 2020

Cancers

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Photodynamic Therapy (PDT) with methyl-aminolevulinate (MAL-PDT) is being used for the treatment of Basal Cell Carcinoma (BCC), although resistant cells may appear. Normal differentiated cells depend primarily on mitochondrial oxidative phosphorylation (OXPHOS) to generate energy, but cancer cells switch this metabolism to aerobic glycolysis (Warburg effect), influencing the response to therapies. We have analyzed the expression of metabolic markers (β-F1-ATPase/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) ratio, pyruvate kinase M2 (PKM2), oxygen consume ratio, and lactate extracellular production) in the resistance to PDT of mouse BCC cell lines (named ASZ and CSZ, heterozygous for ptch1). We have also evaluated the ability of metformin (Metf), an antidiabetic type II compound that acts through inhibition of the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway to sensitize resistant cells to PDT. The results obtained indicated that resistant cells showed an aerobic glycolysis metabolism. The treatment with Metf induced arrest in the G0/G1 phase and a reduction in the lactate extracellular production in all cell lines. The addition of Metf to MAL-PDT improved the cytotoxic effect on parental and resistant cells, which was not dependent on the PS protoporphyrin IX (PpIX) production. After Metf + MAL-PDT treatment, activation of pAMPK was detected, suppressing the mTOR pathway in most of the cells. Enhanced PDT-response with Metf was also observed in ASZ tumors. In conclusion, Metf increased the response to MAL-PDT in murine BCC cells resistant to PDT with aerobic glycolysis.

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Section: Discussionsupporting

confidence: 93%

Metformin as an Adjuvant to Photodynamic Therapy in Resistant Basal Cell Carcinoma Cells

Mascaraque

Delgado-Wicke

Nuevo‐Tapioles

et al. 2020

Cancers

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“…Recently, Li et al (48) demonstrated that metformin can increase the survival rate of diabetic patients with gastric cancer. Previous studies have demonstrated that metformin inhibits cell proliferation and induces cell death in various types of cancer cells, including HepG2 hepatoma cells (49), SKOV3, A2780 and ES2 ovarian cancer cells (50,51), paclitaxel-resistant A2780-PR and cisplatin-resistant ACRP cells (52), B16F10 melanoma cells (53), Dami and MEG-01 megakaryoblastic cancer cells (54), and CAL 27, CAL 33, and UMSCC47 head and neck carcinoma cells (55). Furthermore, metformin also suppresses the cell metastasis of MG63 and U-2 OS osteosarcoma cells (56), SiHa and HeLa cervical cancer cells (57), and EC109 esophageal squamous cells carcinoma cells (58).…”

Section: Discussionmentioning

confidence: 99%

Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling

Chiang²,

Tsai

et al. 2019

Int J Oncol

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Metformin is commonly used to treat patients with type 2 diabetes and is associated with a decreased risk of cancer. Previous studies have demonstrated that metformin can act alone or in synergy with certain anticancer agents to achieve anti-neoplastic effects on various types of tumors via adenosine monophosphate-activated protein kinase (AMPK) signaling. However, the role of metformin in AMPK-mediated apoptosis of human gastric cancer cells is poorly understood. In the current study, metformin exhibited a potent anti-proliferative effect and induced apoptotic characteristics in human AGS gastric adenocarcinoma cells, as demonstrated by MTT assay, morphological observation method, terminal deoxynucleotidyl transferase dUTP nick end labeling and caspase-3/7 assay kits. Western blot analysis demonstrated that treatment with metformin increased the phosphorylation of AMPK, and decreased the phosphorylation of AKT, mTOR and p70S6k. Compound C (an AMPK inhibitor) suppressed AMPK phosphorylation and significantly abrogated the effects of metformin on AGS cell viability. Metformin also reduced the phosphorylation of mitogen-activated protein kinases (ERK, JNK and p38). Additionally, metformin significantly increased the cellular ROS level and included loss of mitochondrial membrane potential (ΔΨm). Metformin altered apoptosis-associated signaling to downregulate the BAD phosphorylation and Bcl-2, pro-caspase-9, pro-caspase-3 and pro-caspase-7 expression, and to upregulate BAD, cytochrome c, and Apaf-1 proteins levels in AGS cells. Furthermore, z-VAD-fmk (a pan-caspase inhibitor) was used to assess mitochondria-mediated caspase-dependent apoptosis in metformin-treated AGS cells. The findings demonstrated that metformin induced AMPK-mediated apoptosis, making it appealing for development as a novel anticancer drug for the treating gastric cancer.

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“…45,49,50 Interestingly, recent studies show that metformin, usually applied in diabetic patients, prevents tumor growth, induces apoptosis and increases sensitivity to chemotherapy in ovarian cancer cells. [51][52][53][54][55][56][57] Mechanisms underlying these cellular effects include suppression of cancer stem cells, inhibition of epithelial-to-mesenchymal transition and interference with neoplastic cell metabolism. [58][59][60][61][62] Following promising data of epidemiological studies showing a favorable effect of metformin on ovarian cancer Figure 6 Summary of the hypothesized interaction within the NRF2/AKR1C1/PR pathway.…”

Section: Discussionmentioning

confidence: 99%

<p>Correlation of NRF2 and progesterone receptor and its effects on ovarian cancer biology</p>

Czogalla¹,

Kahaly²,

Mayr³

et al. 2019

CMAR

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Purpose: This study aimed to investigate the potential prognostic impact of nuclear factor erythroid 2-related factor 2 (NRF2) and progesterone receptor A (PRA)/progesterone receptor B (PRB) in ovarian cancer patients which might be the rationale for putative new treatment strategies. Patients and methods: The presence of NRF2 and PRA/PRB was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC). Staining of NRF2 and PRA/ PRB was rated using the semi-quantitative immunoreactive score (IR score, Remmele's score) and correlated to clinical and pathological data. NRF2 and PRA/PRB expression were compared with respect to the overall survival (OS). Results: NRF2 staining was different in both, the cytoplasm and nucleus between the histological subtypes (p=0.001 and p=0.02, respectively). There was a significant difference in the PRA expression comparing all histological subtypes (p=0.02). Histological subtypes showed no significant differences in the PRB expression. A strong correlation of cytoplasmic NRF2 and PRA expression was detected (cc=0.247, p=0.003) as well as of cytoplasmic NRF2 and PRB expression (cc=0.25, p=0.003), confirmed by immunofluorescence double staining. Cytoplasmic NRF2 expression was associated with a longer OS (median 50.6 vs 32.5 months; p=0.1) as it was seen for PRA expression (median 63.4 vs 33.1 months; p=0.08), although not statistically significant. In addition, high PRB expression (median 80.4 vs 32.5 months; p=0.04) and concurrent expression of cytoplasmic NRF2 and PRA were associated with a significantly longer OS (median 109.7 vs 30.6 months; p=0.02). The same relationship was also noted for NRF2 and PRB with improved OS for patients expressing both cytoplasmic NRF2 and PRB (median 153.5 vs 30.6 months; p=0.009). Silencing of NFE2L2 induced higher mRNA expression of PGR in the cancer cell line OVCAR3 (p>0.05) confirming genetic interactions of NRF2 and PR. Conclusion: In this study, the combination of cytoplasmic NRF2 and high PRA/PRB expression was demonstrated to be associated with improved overall survival in ovarian cancer patients. Further understanding of interactions within the NRF2/AKR1C1/PR pathway could open new additional therapeutic approaches.

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Chemosensitizing effects of metformin on cisplatin- and paclitaxel-resistant ovarian cancer cell lines

Cited by 43 publications

References 29 publications

Metformin as an Adjuvant to Photodynamic Therapy in Resistant Basal Cell Carcinoma Cells

Metformin as an Adjuvant to Photodynamic Therapy in Resistant Basal Cell Carcinoma Cells

Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling

<p>Correlation of NRF2 and progesterone receptor and its effects on ovarian cancer biology</p>

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