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Souvik Datta, PhD

Content writer – Clinical

Effects of metformin as an add-on therapy against Glioblastoma: An old medicine for novel oncology therapeutics.

Published on: June 16, 2022

Original author: Guarnaccia et al., 2022  (doi: 10.3390/cancers14061412)

Medical research is focused on finding solutions through diligent and innovative platforms in the field of health and disease. Every published paper holds a stepping stone toward gaining knowledge and adding a brick in the building of medical advancements. With the improvement in medical sciences and their implementation, globally there has been a drastic reduction in mortality rate as well as an enhancement in the quality of life. Various therapeutic approaches along with the advent of new drugs, bring hope to some incurable diseases of the past.​ In today’s scenario, diseases such as cancers can be life-threatening and impair the lifestyle with a devastating impact on the quality of life of the patients. Glioblastoma multiforme (GBM) is one such form of brain cancer with a dismal prognosis and a poor survival rate. This disease has no curatives, with a median survival of around 14 months. The standard of care treatment for GBM is surgery, followed by temozolomide (TMZ) chemotherapy in tandem with radiation therapy.​ In such a scenario, the need for a new or alternative therapy is essential to combat the rapidly spreading nature of the disease. The major challenge in finding therapeutics in GBM is the presence of unstable mutations which rapidly change the target structures of drugs within the body. This leads to resistance and relapse. Angiogenesis is an event in the progression of such cancers which is the facilitation of rapidly growing cancer cells to metastasize through the formation of blood vessels near the primary site. The new blood vessels or blood capillaries are orchestrated by tumor endothelial cells or Glioblastoma Endothelial Cells (GECs). Thus, recurrences, metastasis, and drug resistance are major problems encountered by clinicians when trying to control this disease. The research seeks for alternative or novel therapeutics to arrest such pathological conditions as a challenge.​ Repurposed drugs are the drugs that are often intended for use in some specific diseases, but in turn, prove to be efficient and useful in other diseases. One such drug is metformin. Metformin (N, N-dimethyl biguanide, MET) is a drug used in diabetic patients to control high blood glucose levels. MET is also called an antihyperglycemic drug. It is fascinating to know that MET administration to diabetic cancer patients has been associated with a reduction in cancer progression incidence. Thus, increasing evidence propose, that the drug can be repurposed to use in cancers, as an add-on therapeutic along with the standard TMZ chemotherapy.​ This research was designed on this backdrop to assess the effectiveness of MET in GBM cells using in vitro study design. The present research paper elucidates the profound potential of a general diabetic drug in arresting cancer cell growth and its aggressiveness via targeting the newly found ‘sphingolipid rheostat’ molecular cascade in the body. Guarnaccia et al. showed that the drug metformin can reduce the progression of GBM-related GECs in a dose and time-dependent manner. Both the treatment options, the combination of TMZ + MET, and MET alone showed a significant decrease in the growth of cancer cells. Finally, a new drug target interaction mechanism was revealed. MET also decreases angiogenesis in GEC cultured cells. Methodology The biopsy samples from ten diagnosed GBM patients were collected and the glioblastoma endothelial cells were cultured in vitro continuously in Dulbecco’s Modified Eagle Medium. The viability of cancer cells was estimated by MTT, and live/dead assay. Similarly, the rate of apoptosis was enumerated by Annexin V staining and caspase 3/7 activity assay. Further, functional tests of angiogenesis include tube-like structure formation as well as a cell migration assay. Finally, quantitative PCR and western blots were conducted to observe the cell-level transcriptomes and the differential expressions in cancer cells. Impact of the research 1. The impact of this research is huge in the perspective of GBM and its implications on diseases like polycystic ovary syndrome and gestational diabetes. 2. MET can be used with TMZ to act synergistically to inhibit the glioblastoma stem cells. MET can also be repurposed for GBM in the future by considering other side effects and dosage in non-diabetic patients. 3. MET will have significance in being a cost-effective and tolerable drug. 4. The combination therapy should take the shape of both pre-clinical and clinical trials to be available in the market. Conclusion Overall, the rationale has been established through this current study to potentiate the use of metformin (MET) therapy primarily as an add-on in patients along with TMZ for future GBM patient management in non-diabetic with optimized doses for enhancing both, the quality of life and survival of the patients.

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