Synergistic effect of metformin and vemurufenib (PLX4032) as a molecular targeted therapy in anaplastic thyroid cancer: an in vitro study

Durai, Latha; Ravindran, Soundharya; Karunagaran, Devarajan; Ramshankar, Vijayalakshmi

doi:10.1007/s11033-021-06762-7

Cited by 8 publications

(9 citation statements)

References 36 publications

(4 reference statements)

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“…Similar results were observed in a follicular rat thyroid cell line, and AMPK modulation of NIS depended in part on the cAMP response element (CRE) present in the NIS promoter [42]. On the other hand, a recent study in ATC cells showed increased NIS mRNA and protein after metformin treatment and increased mRNA of thyroglobulin, TSHR and NKX2.1, as well as metformin acting as a demethylating agent [20]. Thus, more studies are necessary to understand the effect of metformin in iodide uptake in the thyroid cancer context.…”

Section: Thyroid Cancersupporting

confidence: 68%

“…In human ATC and DTC cells, as well as in human thyroid primary cell cultures and rat follicular thyroid cells, metformin antimitogenic activity was correlated with induction of apoptosis and inhibition of cell growth and migration. Some variation was observed depending on the cell line [11][12][13][14][15][16][17][18][19][20][21]. The growth-inhibitory effect of metformin was also observed in thyroid cancer stem cells [11].…”

Section: Thyroid Cancermentioning

confidence: 94%

“…In BCPAP, a similar reduction in cell growth was observed after combined treatment. Recently, synergistic effects leading to p-ERK reduction and p-AMPK increase were obtained in the combination of metformin and vemurafenib in T-238, BCPAP and HTH7 models [20].…”

Section: Thyroid Cancermentioning

confidence: 99%

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Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

2022

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Metformin is the most used drug for type 2 diabetes (T2DM). Its antitumor activity has been described by clinical studies showing reduced risk of cancer development in T2DM patients, as well as management of T2DM compared with those receiving other glucose-lowering drugs. Metformin has a plethora of molecular actions in cancer cells. This review focused on in vitro data on the action mechanisms of metformin on thyroid, prostate and head and neck cancer. AMPK activation regulating specific downstream targets is a constant antineoplastic activity in different types of cancer; however, AMPK-independent mechanisms are also relevant. In vitro evidence makes it clear that depending on the type of tumor, metformin has different actions; its effects may be modulated by different cell conditions (for instance, presence of HPV infection), or it may regulate tissue-specific factors, such as the Na+/I− symporter (NIS) and androgen receptors. The hallmarks of cancer are a set of functional features acquired by the cell during malignant development. In vitro studies show that metformin regulates almost all the hallmarks of cancer. Interestingly, metformin is one of these therapeutic agents with the potential to synergize with other chemotherapeutic agents, with low cost, low side effects and high positive consequences. Some questions are still challenging: Are metformin in vitro data able to translate from bench to bedside? Does metformin affect drug resistance? Can metformin be used as a generic anticancer drug for all types of tumors? Which are the specific actions of metformin on the peculiarities of each type of cancer? Several clinical trials are in progress or have been concluded for repurposing metformin as an anticancer drug. The continuous efforts in the field and future in vitro studies will be essential to corroborate clinical trials results and to elucidate the raised questions.

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Section: Thyroid Cancersupporting

confidence: 68%

Section: Thyroid Cancermentioning

confidence: 94%

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Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

2022

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“…In B-CPAP, a similar decrease in cell growth was reported after combination therapy. In recent times, synergistic effects leading to a decrease in p-ERK and an increase in p-AMPK in the combination of metformin and morafenib were obtained in T-238, BCPAP, and HTH7 models( 34 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of metformin alone and in combination with etoposide and epirubicin on proliferation, apoptosis, necrosis, and migration of B-CPAP and SW cells as thyroid cancer cell lines

Sardari

Ghavami²,

Kiasari³

et al. 2023

Res Pharma Sci

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Background and purpose: There has not been a comprehensive study on the simultaneous effects of metformin, etoposide, and epirubicin on thyroid cancer cells. Hence, the current research proposed the in vitro study on the effect of metformin alone and in combination with etoposide and epirubicin on the rate of proliferation, apoptosis, necrosis, and migration against B-CPAP and SW-1736 cells as thyroid cancer cell lines. Experimental approach: MTT-based proliferation assay, combination index method, flow cytometry, and scratch wound healing assays were used to evaluate the simultaneous effects of the three approved drugs against thyroid cancer cells. Findings/Results: This study showed that the toxic concentration of metformin on normal Hu02 cells was more than 10 folds higher than B-CPAP and SW cancerous cells. Metformin in combination with epirubicin and etoposide could increase percentages of B-CPAP and SW cells in early and late apoptosis and necrosis phases in comparison with their single concentrations, significantly. Metformin in combination with epirubicin and etoposide could arrest the S phase in B-CPAP and SW cells, significantly. Metformin in combination with epirubicin and etoposide could reduce ~100% migration rate, whereas single concentrations of epirubicin and etoposide could reduce ~50% migration rate. Conclusion and implication: Combined treatment of metformin with anticancer drugs epirubicin and etoposide can increase the mortality in thyroid cancer cell lines and reduce the toxicity of these drugs on the normal cell line, which could be the starting point for proposing a new combination strategy in the therapy of thyroid cancer to induce more potency and reduce acute toxicity.

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“…This finding indicates that loss of NAD+ regeneration capacity due to combined treatment with metformin and syrosingopine results in glycolytic blockade, leading to ATP depletion and cell death. A previous study shows that metformin has an in vitro synergistic anticancer effect against anaplastic thyroid cancer when used in combination with vemurafenib [ 41 ].…”

Section: Metabolic Synthetic Lethalitymentioning

confidence: 99%

Development of Metabolic Synthetic Lethality and Its Implications for Thyroid Cancer

Lee

Kang

et al. 2022

Endocrinol Metab

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Cancer therapies targeting genetic alterations are a topic of great interest in the field of thyroid cancer, which frequently harbors mutations in the RAS, RAF, and RET genes. Unfortunately, U.S. Food and Drug Administration-approved BRAF inhibitors have relatively low therapeutic efficacy against BRAF-mutant thyroid cancer; in addition, the cancer often acquires drug resistance, which prevents effective treatment. Recent advances in genomics and transcriptomics are leading to a more complete picture of the range of mutations, both driver and messenger, present in thyroid cancer. Furthermore, our understanding of cancer suggests that oncogenic mutations drive tumorigenesis and induce rewiring of cancer cell metabolism, which promotes survival of mutated cells. Synthetic lethality (SL) is a method of neutralizing mutated genes that were previously considered untargetable by traditional genotype-targeted treatments. Because these metabolic events are specific to cancer cells, we have the opportunity to develop new therapies that target tumor cells specifically without affecting healthy tissue. Here, we describe developments in metabolism-based cancer therapy, focusing on the concept of metabolic SL in thyroid cancer. Finally, we discuss the essential implications of metabolic reprogramming and its role in the future direction of SL for thyroid cancer.

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Synergistic effect of metformin and vemurufenib (PLX4032) as a molecular targeted therapy in anaplastic thyroid cancer: an in vitro study

Cited by 8 publications

References 36 publications

Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

Effect of metformin alone and in combination with etoposide and epirubicin on proliferation, apoptosis, necrosis, and migration of B-CPAP and SW cells as thyroid cancer cell lines

Development of Metabolic Synthetic Lethality and Its Implications for Thyroid Cancer

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