Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median su...
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MDPI AG
2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/15/8083 |
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| author | Sumit Siddharth Panjamurthy Kuppusamy Qitong Wu Arumugam Nagalingam Neeraj K. Saxena Dipali Sharma |
| author_facet | Sumit Siddharth Panjamurthy Kuppusamy Qitong Wu Arumugam Nagalingam Neeraj K. Saxena Dipali Sharma |
| author_sort | Sumit Siddharth |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects. |
| first_indexed | 2024-03-09T05:24:16Z |
| format | Article |
| id | doaj.art-5f9a4923de644b8d94321cc2b401605e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T05:24:16Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5f9a4923de644b8d94321cc2b401605e2023-12-03T12:38:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012315808310.3390/ijms23158083Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular CarcinomaSumit Siddharth0Panjamurthy Kuppusamy1Qitong Wu2Arumugam Nagalingam3Neeraj K. Saxena4Dipali Sharma5Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USADepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USADepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USANational Cancer Institute, National Institutes of Health, Rockville, MD 20850, USADepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USAHepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.https://www.mdpi.com/1422-0067/23/15/8083hepatocellular carcinomacombination treatmentsorafenibmetforminMAPKERK |
| spellingShingle | Sumit Siddharth Panjamurthy Kuppusamy Qitong Wu Arumugam Nagalingam Neeraj K. Saxena Dipali Sharma Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma International Journal of Molecular Sciences hepatocellular carcinoma combination treatment sorafenib metformin MAPK ERK |
| title | Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma |
| title_full | Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma |
| title_fullStr | Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma |
| title_full_unstemmed | Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma |
| title_short | Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma |
| title_sort | metformin enhances the anti cancer efficacy of sorafenib via suppressing mapk erk stat3 axis in hepatocellular carcinoma |
| topic | hepatocellular carcinoma combination treatment sorafenib metformin MAPK ERK |
| url | https://www.mdpi.com/1422-0067/23/15/8083 |
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