Metformin in combination with cisplatin inhibits cell viability and induces apoptosis of human ovarian cancer cells by inactivating ERK 1/2

Dang, Jianhong; Jin, Zhendong; Liu, Xiaojun; Hu, Dian; Wang, Jing; Luo, Yan; Li, Ling‐Ling

doi:10.3892/ol.2017.7176

Cited by 24 publications

(27 citation statements)

References 28 publications

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“…Our results are in agreement with a study showing enhanced chemosensitivity of ovarian cancer cisplatin-resistant cells following treatment with BEZ235, which was accompanied by marked attenuation of PI3K/AKT pathway [46]. A recent study suggested that metformin combined with cisplatin impeded cell viability and caused apoptosis by inactivating ERK 1/2 in human ovarian cancer cells [49].…”

Section: Discussionsupporting

confidence: 93%

Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

et al. 2020

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Initially, patients that respond to cisplatin (DDP) treatment later relapse and develop chemoresistance. Agents that enhance DDP effectiveness will have a significant impact on cancer treatment. We have shown pronounced inhibitory effects of the progesterone-calcitriol combination on endometrial and ovarian cancer cell growth. Here, we examined whether and how progesterone-calcitriol combination potentiates DDP anti-tumor effects in cancer cells. Ovarian and endometrial cancer cells treated with various concentrations of DDP showed a concentration-dependent decrease in cell proliferation. Concurrent treatment of cells with DDP and progesterone-calcitriol ombination potentiated anticancer effects of DDP compared to DDP-calcitriol, or DDP-progesterone treated groups. The anticancer effects were mediated by increased caspase-3, BAX, and decreased BCL2 and PARP-1 expression in DDP and progesterone-calcitriol combination-treated cells. Stimulation of the PI3K/AKT and MAPK/ERK pathways seen in cancer cells was reduced in DDP-progesterone-calcitriol treated cells. Pretreatment of cells with specific inhibitors further diminished AKT and ERK expression. Furthermore, progesterone-calcitriol potentiated the anti-growth effects of DDP on cancer cells by attenuating the expression of SMAD2/3, multidrug resistance protein- 1 (MDR-1), and ABC transporters (ABCG1, and ABCG2), thereby impeding the efflux of chemo drugs from cancer cells. These results suggest a potential clinical benefit of progesterone-calcitriol combination therapy when used in combination with DDP.

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Section: Discussionsupporting

confidence: 93%

Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

et al. 2020

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“…Moreover, several studies have suggested that inhibition of the MEK/ERK pathway disrupts functions essential for ovarian cancer progression (29,35,37). Dang et al (39) reported that metformin in combination with cisplatin inhibits cell viability and induces apoptosis of human ovarian cancer cells by inactivating ERK. In another study, Chan et al (40) demonstrated that therapies targeting the ERK signaling pathway reduce the aggressiveness of ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 99%

SPARCL1 suppresses the proliferation and migration of human ovarian cancer cells via the MEK/ERK signaling

2018

Exp Ther Med

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Ovarian cancer is the most lethal gynecological malignancy worldwide and is one of the five leading causes of cancer-associated mortality in women. There is an urgent requirement to obtain a greater understanding of the molecular mechanism underlying ovarian cancer progression in order to identify novel drug targets and biomarkers. Secreted protein acidic and rich in cysteine-like protein 1 (SPARCL1) has been suggested as a candidate tumor suppressor in various types of human cancers. However, the potential role of SPARCL1 for ovarian cancer has not yet been clearly established. In the present study, lower protein expression levels of SPARCL1 were detected in ovarian cancer tissues when compared with adjacent normal tissues. Overexpression of SPARCL1 significantly suppressed the proliferation and migration of cells from the ovarian cancer cell line SKOV-3, whereas knockdown of SPARCL1 significantly increased cell growth and migration. Furthermore, the results revealed that SPARCL1 overexpression significantly suppressed the activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway. Collectively, these results indicated that SPARCL1 may suppress the proliferation and migration of ovarian cancer cells by downregulating signaling via the MEK/ERK pathway.

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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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Metformin in combination with cisplatin inhibits cell viability and induces apoptosis of human ovarian cancer cells by inactivating ERK 1/2

Cited by 24 publications

References 28 publications

Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

SPARCL1 suppresses the proliferation and migration of human ovarian cancer cells via the MEK/ERK signaling

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

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