Impairment of electron transport chain and induction of apoptosis by chrysin nanoparticles targeting succinate-ubiquinone oxidoreductase in pancreatic and lung cancer cells

Abstract

Background Flavonoids may help ameliorate the incidence of the major causes of tumor-related mortality, such as pancreatic ductal adenocarcinoma (PDAC) and lung cancer, which are predicted to steadily increase between 2020 to 2030. Here we compared the effect of chrysin and chrysin nanoparticles (CCNPs) with 5-fluorouracil (5-FLU) on the activity and expression of mitochondrial complex II (CII) to induce apoptosis in pancreatic (PANC-1) and lung (A549) cancer cells. Methods Chrysin nanoparticles (CCNPs) were synthesized and characterized, and the IC50 was evaluated in normal, PANC-1, and A549 cell lines using the MTT assay. The effect of chrysin and CCNPs on CΙΙ activity, superoxide dismutase activity, and mitochondria swelling were evaluated. Apoptosis was assessed using flow cytometry, and expression of the C and D subunits of SDH, sirtuin-3 (SIRT-3), and hypoxia-inducible factor (HIF-1α) was evaluated using RT-qPCR. Results The IC50 of CII subunit C and D binding to chrysin was determined and used to evaluate the effectiveness of treatment on the activity of SDH with ubiquinone oxidoreductase. Enzyme activity was significantly decreased (chrysin < CCNPs < 5-FLU and CCNPs < chrysin < 5-FLU, respectively), which was confirmed by the significant decrease of expression of SDH C and D, SIRT-3, and HIF-1α mRNA (CCNPs < chrysin < 5-FLU). There was also a significant increase in the apoptotic effects (CCNPs > chrysin > 5-FLU) in both PANC-1 and A549 cells and a significant increase in mitochondria swelling (CCNPs < chrysin < 5-FLU and CCNPs > chrysin > 5-FLU, respectively) than that in non-cancerous cells. Conclusion Treatment with CCNPs improved the effect of chrysin on succinate-ubiquinone oxidoreductase activity and expression and therefore has the potential as a more efficient formulation than chemotherapy to prevent metastasis and angiogenesis by targeting HIF-1α in PDAC and lung cancer.

Chrysin Inhibits TAMs-Mediated Autophagy Activation via CDK1/ULK1 Pathway and Reverses TAMs-Mediated Growth-Promoting Effects in Non-Small Cell Lung Cancer

“…Lirdprapamongkol et al found through in vivo and in vitro experiments that chrysin can inhibit breast cancer proliferation under hypoxic conditions and reduce breast cancer lung metastasis [ 44 ]. Also, chrysin could promote apoptosis in lung cancer cells and increase their sensitivity to chemotherapy drugs [ 45 , 46 ]. In this study, we explored the anti-tumor effect of chrysin at the molecular level through in vivo and in vitro experiments.…”

Comprehensive overview of how to fade into succinate dehydrogenase dysregulation in cancer cells by naringenin-loaded chitosan nanoparticles

“…SDH catalyzes the conversion of succinate to fumarate in the TCA cycle and carries electrons to the respiratory chain's ubiquinone (coenzyme Q) pool. The catalytic subunits in the hydrophilic head of SDH that extend into the mitochondrial matrix are subunits A (SDHA) and B (SDHB) [ 44 ]. These activities are carried out by the membrane-anchoring and ubiquinone-binding SDH subunits, SDHC, and SDHD, respectively as illustrated in (Fig.…”

“…Lately, there has been a growing interest in the use of natural compounds that can hinder tumor-specific alterations in mitochondrial metabolism. These substances have the potential to serve as an appealing therapeutic approach for triggering the activation of the cellular death process in cancer cells [ 25 , 44 , 49 ]. Flavonoids are commonly found in fruits, vegetables, and a variety of herbal preparations.…”

“…Our previous studies suggest that CS capsulate flavonoid drugs make it targeted to specific sites on SDH especially at the UbQ-binding site between the SDHC and SDHD subunits in recent research, which demonstrated that they greatly inhibited SDH activity in cancer cells [ 42 , 44 , 49 , 53 ].…”

The Regulation Impact of Naringenin-loaded Chitosan Nanoparticles on Succinate Dehydrogenase Activity in Cancer Cells

“…Recently, natural substances have attention due to block tumor-specific changes in the mitochondrial metabolism and could be an attractive therapeutic strategy for activating the cell death machinery in cancer cells [47][48][49]. Flavanone group member naringenin (NAR) [2,3-dihydro-5,7-dihydroxy-2-(4hydroxyphenyl)-4H-1-benzopyran-4-one) was discovered by Power and Tutin in 1907 [50].…”