TY - JOUR
T1 - A combination of metformin and epigallocatechin gallate potentiates glioma chemotherapy in vivo
AU - Kuduvalli, Shreyas S.
AU - Daisy, Precilla S.
AU - Vaithy, Anandraj
AU - Purushothaman, Mugilarasi
AU - Ramachandran Muralidharan, Arumugam
AU - Agiesh, Kumar B.
AU - Mezger, Markus
AU - Antony, Justin S.
AU - Subramani, Madhu
AU - Dubashi, Biswajit
AU - Biswas, Indrani
AU - Guruprasad, K. P.
AU - Anitha, T. S.
N1 - Funding Information:
We would like to thank Prof. Adithan C, Former Dean-Research, Sri Balaji Vidyapeeth for providing Vany Adithan Research Fellowship for the first author. We would also like to acknowledge Prof. K Satyamoorthy, Director, Manipal School of Life Sciences, MAHE, Manipal, for providing the animal facility to carry out our objective. We acknowledge Centre for Stem Cell Research (a unit of inStem, Bengaluru), CMC Campus, Vellore, India for providing flow-cytometry facility. We express our gratitude towards Sri Balaji Vidyapeeth for providing the basic laboratory and instrumentation facilities. We would also like to thank Guillermo Urena-Bailen for the graphical illustration.
Publisher Copyright:
Copyright © 2023 Kuduvalli, Daisy, Vaithy, Purushothaman, Ramachandran Muralidharan, Agiesh, Mezger, Antony, Subramani, Dubashi, Biswas, Guruprasad and Anitha.
PY - 2023
Y1 - 2023
N2 - Glioma is the most devastating high-grade tumor of the central nervous system, with dismal prognosis. Existing treatment modality does not provide substantial benefit to patients and demands novel strategies. One of the first-line treatments for glioma, temozolomide, provides marginal benefit to glioma patients. Repurposing of existing non-cancer drugs to treat oncology patients is gaining momentum in recent years. In this study, we investigated the therapeutic benefits of combining three repurposed drugs, namely, metformin (anti-diabetic) and epigallocatechin gallate (green tea-derived antioxidant) together with temozolomide in a glioma-induced xenograft rat model. Our triple-drug combination therapy significantly inhibited tumor growth in vivo and increased the survival rate (50%) of rats when compared with individual or dual treatments. Molecular and cellular analyses revealed that our triple-drug cocktail treatment inhibited glioma tumor growth in rat model through ROS-mediated inactivation of PI3K/AKT/mTOR pathway, arrest of the cell cycle at G1 phase and induction of molecular mechanisms of caspases-dependent apoptosis.In addition, the docking analysis and quantum mechanics studies performed here hypothesize that the effect of triple-drug combination could have been attributed by their difference in molecular interactions, that maybe due to varying electrostatic potential. Thus, repurposing metformin and epigallocatechin gallate and concurrent administration with temozolomide would serve as a prospective therapy in glioma patients.
AB - Glioma is the most devastating high-grade tumor of the central nervous system, with dismal prognosis. Existing treatment modality does not provide substantial benefit to patients and demands novel strategies. One of the first-line treatments for glioma, temozolomide, provides marginal benefit to glioma patients. Repurposing of existing non-cancer drugs to treat oncology patients is gaining momentum in recent years. In this study, we investigated the therapeutic benefits of combining three repurposed drugs, namely, metformin (anti-diabetic) and epigallocatechin gallate (green tea-derived antioxidant) together with temozolomide in a glioma-induced xenograft rat model. Our triple-drug combination therapy significantly inhibited tumor growth in vivo and increased the survival rate (50%) of rats when compared with individual or dual treatments. Molecular and cellular analyses revealed that our triple-drug cocktail treatment inhibited glioma tumor growth in rat model through ROS-mediated inactivation of PI3K/AKT/mTOR pathway, arrest of the cell cycle at G1 phase and induction of molecular mechanisms of caspases-dependent apoptosis.In addition, the docking analysis and quantum mechanics studies performed here hypothesize that the effect of triple-drug combination could have been attributed by their difference in molecular interactions, that maybe due to varying electrostatic potential. Thus, repurposing metformin and epigallocatechin gallate and concurrent administration with temozolomide would serve as a prospective therapy in glioma patients.
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U2 - 10.3389/fphar.2023.1096614
DO - 10.3389/fphar.2023.1096614
M3 - Article
AN - SCOPUS:85151757050
SN - 1663-9812
VL - 14
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 1096614
ER -
