Insights into the Therapeutic Outcomes of Trimetazidine/doxorubicin Combination in Ehrlich Solid-Phase Carcinoma Mouse Tumor Model

One of the key features of cancer is metabolic reprogramming that can be exploited to sensitize cancer cells to chemotherapy. Trimetazidine (TMZ) is a metabolic anti-ischemic drug that blocks the activity of long-chain 3ketoacyl CoA thiolase leading to the inhibition of fatty acid oxidation.Aims: The objective of the current investigation was to evaluate the idea that TMZ could synergize the antitumor activity of doxorubicin (DOX).Main methods: The hypothesis was examined in vitro using the human breast cancer cell lines MCF-7 and MDAMB231. In addition, the in vivo experiments were conducted using the Ehrlich solid phase carcinoma model.Key findings: In vitro cytotoxicity experiments demonstrated that TMZ improved the potency of DOX in MCF-7 cell lines in a synergistic manner. In vivo testing confirmed that DOX/TMZ combination exhibits synergistic effect at both DOX/TMZ 1:10 and 1:5 ratios, where DOX was administered at one tenth and one fifth of its original dose, respectively. The co-treatment (1:5 ratio) significantly reduced tumor Nicotinamide adenine dinucleotide (NAD)+/NADH ratio (6.1-fold) and Adenosine triphosphate (ATP) levels (61 %) with concurrent activation of AMP-activated protein kinase (AMPK) (2.2-fold) and peroxisome proliferator-activated receptorgamma coactivator (PGC)1-a (5.5-fold) protein expression versus control. The same treatment decreased the nuclear levels of NF-?B (p65) (57.5 %) and induced tumor apoptosis as evidenced by elevated Bax/Bcl-2 ratio (6.8-fold) along with active caspase-3 levels (6.6-fold) against control. Significance: The current investigation constitutes a proof-of-concept study that provided preclinical evidence for the anticancer activity of DOX/TMZ combination and warrants further investigation for repurposing TMZ in DOX protocols.