title: Naringenin Ameliorates Doxorubicin Toxicity and Hypoxic Condition in Dalton's Lymphoma Ascites Tumor Mouse Model: Evidence from Electron Paramagnetic Resonance Imaging.
abstract: Doxorubicin (DOX) is a well-known cytotoxic agent used extensively as a chemotherapeutic drug to eradicate a wide variety of human cancers. Reactive oxygen species (ROS)-mediated oxidative stress during DOX treatment can induce cardiac, renal, and hepatic toxicities, which can constrain its use as a potential cytotoxic agent. The present work investigates the antioxidant potential of naringenin (NAR) against DOXinduced toxicities of a Dalton's lymphoma ascites (DLA) tumor-bearing mouse model. Mice were randomized into four groups: a negative control, positive control, DOX (2.5 mg/kg) treated, and DOX (2.5 mg/kg) + NAR (50 mg/kg/d) treated. DOX administration significantly altered the levels of functional markers in blood and antioxidant enzymes in kidney, heart, lung, liver, spleen, and tumor tissues. These changes in antioxidant enzymes and successive lipid peroxidation were prevented by NAR supplementation, resulting in decreases in the risk of toxicity due to DOX therapy. Histopathology results and electron paramagnetic resonance imaging (EPRI) of the tumor microenvironment confirmed this evidence. Using EPRI, pharmacokinetics of the nitroxide, 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (3-CP) was monitored intratumorally before and after chemotherapy. EPRI of the DOX + NAR-treated mouse model showed reduced tumor size with significant modification of the hypoxic condition inside the tumor microenvironment. Consequently, these findings suggest that NAR treatment significantly reduces DOX-induced toxicity and the hypoxic condition in a DLA tumor-bearing mouse model.
authors.affiliation: School of Biological Sciences, Madurai Kamaraj University, Madurai-625 021, India; School of Chemistry, Madurai Kamaraj University, Madurai-625 021, India.
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Kathiresan
authors.affiliation: School of Biological Sciences, Madurai Kamaraj University, Madurai-625 021, India.
authors.forename: Swathika
authors.initials: S
authors.lastname: Subburaman
authors.affiliation: University Science Instrumentation Centre, Madurai Kamaraj University, Madurai-625 021, India.
authors.forename: Arun Venkatesh
authors.initials: AV
authors.lastname: Krishna
authors.affiliation: University Science Instrumentation Centre, Madurai Kamaraj University, Madurai-625 021, India.
authors.forename: Mathivanan
authors.initials: M
authors.lastname: Natarajan
authors.affiliation: School of Chemistry, Madurai Kamaraj University, Madurai-625 021, India.
authors.forename: Gandhidasan
authors.initials: G
authors.lastname: Rathinasamy
authors.affiliation: School of Biological Sciences, Madurai Kamaraj University, Madurai-625 021, India.
authors.forename: Kumaresan
authors.initials: K
authors.lastname: Ganesan
authors.affiliation: School of Biological Sciences, Madurai Kamaraj University, Madurai-625 021, India; School of Chemistry, Madurai Kamaraj University, Madurai-625 021, India; Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Chennai-603 103, India.
authors.forename: Murugesan
authors.initials: M
authors.lastname: Ramachandran
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation / Q000187:drug effects; D044950:Flavanones / Q000494:pharmacology*; D000860:Hypoxia / Q000188:drug therapy*; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D010088:Oxidoreductases / Q000378:metabolism; D011759:Pyrrolidines / Q000493:pharmacokinetics; D011897:Random Allocation
chemical_list: D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D044950:Flavanones; D011759:Pyrrolidines; D004317:Doxorubicin; D010088:Oxidoreductases; C005273:naringenin