Metformin enhances the radiosensitivity of human liver cancer cells to γ-rays and carbon ion beams

Kim, Eun Ho; Kim, Misook; Furusawa, Yoshiya; Uzawa, Akiko; Han, Su Cheol; Jung, Woo-Hwan; Sai, Sei

doi:10.18632/oncotarget.12966

Cited by 15 publications

(11 citation statements)

References 46 publications

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“…Role of 12 C ion in EMT is largely an unexplored area. 12 C ion reduces vimentin and anillin in different cells [9, 11]. Generally, N-cadherin, vimentin and anillin facilitates EMT whereas claudin-1, − 2 opposes EMT process.…”

Section: Discussionmentioning

confidence: 99%

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Reduction of metastatic potential by inhibiting EGFR/Akt/p38/ERK signaling pathway and epithelial-mesenchymal transition after carbon ion exposure is potentiated by PARP-1 inhibition in non-small-cell lung cancer

et al. 2019

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Background Carbon ion ( 12 C) radiotherapy is becoming very promising to kill highly metastatic cancer cells keeping adjacent normal cells least affected. Our previous study shows that combined PARP-1 inhibition with 12 C ion reduces MMP-2,-9 synergistically in HeLa cells but detailed mechanism are not clear. To understand this mechanism and the rationale of using PARP-1 inhibitor with 12 C ion radiotherapy for better outcome in controlling metastasis, we investigated metastatic potential in two non-small cell lung cancer (NSCLC) A549 and H1299 (p53-deficient) cells exposed with 12 C ion in presence and absence of PARP-1 inhibition using siRNA or olaparib. Methods We monitored cell proliferation, in-vitro cell migration, wound healing, expression and activity of MMP-2, − 9 in A549 and p53-deficient H1299 cell lines exposed with 12 C ion with and without PARP-1 inhibitor olaparib/DPQ. Expression and phosphorylation of NF-kB, EGFR, Akt, p38, ERK was also observed in A549 and H1299 cells exposed with 12 C ion with and without PARP-1 inhibition using siRNA or olaparib. We also checked expression of few marker genes involved in epithelial-mesenchymal transition (EMT) pathways like N-cadherin, vimentin, anillin, claudin-1, − 2 in both NSCLC. To determine the generalized effect of 12 C ion and olaparib in inhibition of cell’s metastatic potential, wound healing and activity of MMP-2, − 9 was also studied in HeLa and MCF7 cell lines after 12 C ion exposure and in combination with PARP-1 inhibitor olaparib. Results Our experiments show that 12 C ion and PARP-1 inhibition separately reduces cell proliferation, cell migration, wound healing, phosphorylation of EGFR, Akt, p38, ERK resulting inactivation of NF-kB. Combined treatment abolishes NF-kB expression and hence synergistically reduces MMP-2, − 9 expressions. Each single treatment reduces N-cadherin, vimentin, anillin but increases claudin-1, − 2 leading to suppression of EMT process. However, combined treatment synergistically alters these proteins to suppress EMT pathways significantly. Conclusion The activation pathways of transcription of MMP-2,-9 via NF-kB and key marker proteins in EMT pathways are targeted by both 12 C ion and olaparib/siRNA. Hence, 12 C ion radiotherapy could potentially be combined with olaparib as chemotherapeutic agent for better control of cancer metastasis. Electronic supplementary material The online version of this article (10.1186/s12885-019-6015-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…During EMT, there is secretion and activation of Matrix metalloproteinases (MMPs) that cleave extracellular matrix (ECM) to help these transformed cells to invade or migrate [8]. Unlike to gamma, 12 C ion radiotherapy reduces invasiveness and metastatic potential although the detailed mechanisms are still unresolved [9–11].…”

Section: Introductionmentioning

confidence: 99%

Reduction of metastatic potential by inhibiting EGFR/Akt/p38/ERK signaling pathway and epithelial-mesenchymal transition after carbon ion exposure is potentiated by PARP-1 inhibition in non-small-cell lung cancer

et al. 2019

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“…Thus far, it is estimated that more than 16,000 patients have received 12 C 6þ treatment. In spite of the fact that 12 C 6þ radiotherapy can be applied for cervical cancer treatment, there are still some limitations for haematological diseases, tumours around vital organs and patients with distant metastases [16,17]. Therefore, the identification of high-efficiency and low-toxic radiation sensitizers for cancer to improve the radiosensitivity is required.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells

Zhang

Gan

et al. 2020

Artificial Cells, Nanomedicine, and Biotechnology

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Cervical cancer is the second most common malignant tumour threatening women's health. In recent years, heavy-ion beam therapy is becoming a newly emerging therapeutic mean of cancer; however, radio-resistance and radiation-induced damage constitute the main obstacles for curative treatment of cervical cancer. Therefore, to identify the radiosensitizers is essential. Here, we investigated the effects of Wnt signalling pathway on the response of 12 C 6þ radiation in HeLa cells. XAV939, an inhibitor of Wnt signalling pathway, was added two hours before 12 C 6þ radiation. 12 C 6þ radiation inhibited the viability of HeLa cells in a time-dependent manner, and inhibiting Wnt signalling using XAV939 significantly intensified this stress. Meanwhile, 12 C 6þ radiation induced a significant increased cell apoptosis, G2/M phase arrest, and the number of c-H2AX foci. Supplementation with XAV939 significantly increased the effects induced by 12 C 6þ radiation alone. Combining XAV939 with 12 C 6þ irradiation, the expression of apoptotic genes (p53, Bax, Bcl-2) was significantly increased, while the expression of Wnt-related genes (Wnt3a, Wnt5a, b-catenin, cyclin D1 and c-Myc) was significantly decreased. Overall, these findings suggested that blockage of the Wnt/b-catenin pathway effectively sensitizes HeLa cells to 12 C 6þ irradiation, and it may be a potential therapeutic approach in terms of increasing the clinical efficacy of 12 C 6þ beams.

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“…Metformin also inhibited cell proliferation, invasion, angiogenesis, and induced apoptosis in HCC [ 14 – 17 ]. Metformin also enhanced the effect of sorafenib, arsenic trioxide and 5-fluorouracil, and reversed multidrug resistance of HCC [ 18 – 22 ]. Whether metformin could be used to inhibit the growth of HCC after insufficient RFA and further prevent the progression of residual HCC remains unclearly.…”

Section: Introductionmentioning

confidence: 99%

Metformin exhibits the anti-proliferation and anti-invasion effects in hepatocellular carcinoma cells after insufficient radiofrequency ablation

et al. 2017

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BackgroundThe mechanisms and prevention of progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA) has been preliminarily investigated, therefore, new strategy needs to be investigated to prevent the process. Whether metformin could be used to inhibit the growth of HCC after insufficient RFA and further prevent the progression of residual HCC remains unclearly.MethodsMTT assay, colony formation assay and transwell assay were used to observe the cell viability, migration and invasion. Western blot and immunohistochemistry methods were used to observe the expression of proteins. Xenograft model was used to evaluate the growth of HCC cells in vivo.ResultsMetformin inhibited the enhanced proliferation, migration and invasion of HepG2 and SMMC7721 cells after insufficient RFA (named as HepG2-H and SMMC7721-H). Metformin deregulated the expression of p-Akt in HepG2 and SMMC7721 cells after insufficient RFA through AMPK/PTEN pathway. HepG2-H cells also exhibited larger tumor size in vivo. Higher expression of Ki-67 and CD31 and lower expression of E-cadherin were observed in HepG2-H tumors. Metformin blocked the enhanced growth of HepG2 cells in vivo after insufficient RFA. Metformin had no apparent toxicity on nude mice.ConclusionsMetfromin inhibited the growth of HCC cells after insufficient RFA, and may be used to prevent the progression of HCC after RFA.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-017-0418-6) contains supplementary material, which is available to authorized users.

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Metformin enhances the radiosensitivity of human liver cancer cells to γ-rays and carbon ion beams

Cited by 15 publications

References 46 publications

Reduction of metastatic potential by inhibiting EGFR/Akt/p38/ERK signaling pathway and epithelial-mesenchymal transition after carbon ion exposure is potentiated by PARP-1 inhibition in non-small-cell lung cancer

Reduction of metastatic potential by inhibiting EGFR/Akt/p38/ERK signaling pathway and epithelial-mesenchymal transition after carbon ion exposure is potentiated by PARP-1 inhibition in non-small-cell lung cancer

Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells

Metformin exhibits the anti-proliferation and anti-invasion effects in hepatocellular carcinoma cells after insufficient radiofrequency ablation

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