Benzo[a]pyrene treatment modulates Nrf2/Keap1 axis and changes the metabolic profile in rat lung cancer

Washimkar, Kaveri R.; Tomar, Manendra Singh; Ishteyaque, Sharmeen; Kumar, Akhilesh; Shrivastava, Ashutosh; Mugale, Madhav Nilakanth

doi:10.1016/j.cbi.2023.110373

Cited by 9 publications

(8 citation statements)

References 55 publications

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“…Since our findings confirmed that mitochondrial ROS production and the mitochondrially mediated intrinsic apoptotic pathway are involved in B(a)P-induced toxicity, we went further to study the mitochondrial membrane potential (MMP) and activities of the respiratory enzyme complexes and their bioenergetics. Consistent with other studies [3,10,39,40,48,49], we also observed a three-to four-fold loss of membrane potential after B(a)P treatment, followed by the release of cytochrome c into the cytosol. AZD treatment abrogated the loss and brought the values close to control levels.…”

Section: Discussionsupporting

confidence: 93%

“…A reduction in mitochondrial ROS with AZD treatment was confirmed using a ROS-sensitive, mitochondrial-specific fluorogenic probe, CM-H2XRos (Mito Tracker ® Red), which specifically measures the intracellular production of hydrogen peroxide. Studies have shown the increased cellular content of MDA after treatment with B(a)P, indicating increased oxidative stress [6,39,[41][42][43]. Our study also confirmed increased MDA levels after B(a)P treatment, which were alleviated in the presence of AZD.…”

Section: Discussionsupporting

confidence: 86%

“…Many studies have reported B(a)P-stimulated oxidative stress caused by intracellular ROS production, lipid peroxidation, and alterations in anti-oxidant enzymes in vitro and in vivo [3,6,39,40]. Our findings also demonstrated increased oxidative/nitrosative stress in HepG2 cells treated with 25 µM B(a)P for 24 h and its attenuation with AZD.…”

Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

“…The first physiological line of defense against oxidative stress comprises anti-oxidant enzymes including SOD, catalase, GSH, and GSH-metabolizing enzymes [39]. B(a)P administration has been shown to suppress SOD activity [6,39,40,44], indicating increased oxidative stress. Our study also showed decreased SOD activity and increased catalase activity in the cells treated with B(a)P, which were regulated after AZD treatment.…”

Section: Discussionmentioning

confidence: 99%

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Azadirachtin Attenuates Carcinogen Benzo(a) Pyrene-Induced DNA Damage, Cell Cycle Arrest, Apoptosis, Inflammatory, Metabolic, and Oxidative Stress in HepG2 Cells

John,

Raza

2023

Antioxidants

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Azadirachtin (AZD), a limonoid from the versatile, tropical neem tree (Azadirachta indica), is well known for its many medicinal, and pharmacological effects. Its effects as an anti-oxidant, anti-inflammatory, and anti-cancer agent are well known. However, not many studies have explored the effects of AZD on toxicities induced by benzo(a)pyrene (B(a)P), a toxic component of cigarette smoke known to cause DNA damage and cell cycle arrest, leading to different kinds of cancer. In the present study, using HepG2 cells, we investigated the protective effects of Azadirachtin (AZD) against B(a)P-induced oxidative/nitrosative and metabolic stress and mitochondrial dysfunction. Treatment with 25 µM B(a)P for 24 h demonstrated an increased production of reactive oxygen species (ROS), followed by increased lipid peroxidation and DNA damage presumably, due to the increased metabolic activation of B(a)P by CYP 450 1A1/1A2 enzymes. We also observed intrinsic and extrinsic apoptosis, alterations in glutathione-dependent redox homeostasis, cell cycle arrest, and inflammation after B(a)P treatment. Cells treated with 25 µM AZD for 24 h showed decreased oxidative stress and apoptosis, partial protection from DNA damage, and an improvement in mitochondrial functions and bioenergetics. The improvement in antioxidant status, anti-inflammatory potential, and alterations in cell cycle regulatory markers qualify AZD as a potential therapeutic in combination with anti-cancer drugs.

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