Cefixime; a cephalosporin antibiotic, triggers mitochondrial-mediated cell death via mitochondrial permeability transition pore opening in male Wistar rats
DOI:
https://doi.org/10.4314/ajbr.v27i1.17Keywords:
Cefixime, mitochondria, apoptosis, cancerAbstract
Background: Inducers or inhibitors of opening of the Mitochondrial Permeability Transition (mPT) Pore are targets of drug development for conditions arising from dysregulated apoptosis. Some antibiotics have been shown to effect anticancer property by induction of mitochondrial-mediated cell death via mPT pore opening. This study therefore investigated the effect of cefixime; a cephalosporin antibiotic on mitochondrial-mediated cell death via mPT pore using rat model.
Methods: Thirty male Wistar strain rats were randomly assigned into five equal groups; group I is the control while groups II, III, IV and V were orally treated with cefixime (10, 20, 30 and 40mg/kg) daily for two weeks. Mitochondria were isolated by differential centrifugation. The opening of the pore, cytochrome c release, mitochondrial ATPase (mATPase) activity, mitochondrial lipid peroxidation (mLPO), caspases 3 and 9 activities and hepatic DNA fragmentation were determined.
Results: Varying concentrations of cefixime caused induction of mPT pore opening, cytochrome c release and mATPase activity in a concentration-dependent manner. Similarly, oral administration of cefixime caused dose-dependent induction of mPT pore opening, mATPase activity, mitochondrial lipid peroxidation (mLPO) and caspases 3 and 9 activation and hepatic DNA fragmentation.
Conclusion: These results suggests that cefixime; a cephalosporin antibiotic, triggers mitochondrial-mediated cell death via mitochondrial permeability transition pore opening in male Wistar rats. Its anticancer potential should further be explored
References
Andries, K., Verhasselt, P., Guillemont, J., Gohlmann, H. W., Neefs, J. M., Winkler, H., van Gestel, J., Timmerman, P., Zhu, M., Lee, E., Williams, P., de Chaffoy, D., Huitric, E., Hoffner, S., Cambau, E., et al. (2005). A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307(5707): 223–227.
Appaix, F., Minatchy, M., Riva-Lavieille, C., Olivaires, J., Antonnson, B., and Saks, V. A. (2000). Rapid spectrophotometric method for quantitation of cyctochrome c release from isolated mitochondria or permeabilized cells revisited. Biochimica et Biophysica Acta, 1457: 175–181.
Bauer, T.M., Murphy, E. (2020). Role of mitochondrial calcium and the permeability transition pore in regulating cell death. Circulation Research, 126(2): 280–293.
Bock, F.J., Tait, S.W.G. (2020). “Mitochondria as multifaceted regulators of cell death,” Nature Reviews Molecular Cell Biology, 21 (2): 85–100.
Bonora, M., Wieckowski, M.R., Chinopoulos, C., Kepp, O., Kroemer, G., Galluzzi, L., Pinton, P. (2015). Molecular mechanisms of cell death: Central implication of ATP synthase in mitochondrial permeability transition. Oncogene, 34: 1475–1486.
Dejean, L.M., Martinez-Caballero, S., Manon, S., Kinnally, K.W. (2006). Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins. Biochim. Biophys. Acta, 1762: 191–201.
Garrido,C., Galluzzi, L., Brunet, M., Puig, P.E., Didelot, C., Kroemer, G. (2006). “Mechanisms of cytochrome _c_ release from mitochondria,” Cell Death and Differentiation, 13(9): 1423–1433.
Giampaolo Morciano, Natalia Naumova, Piotr Koprowski, Sara Valente, Vilma A. Sardão, Yaiza Potes, Alessandro Rimessi, Mariusz R. Wieckowski, Paulo J. Oliveira. (2021). The mitochondrial permeability transition pore: an evolving concept critical for cell life and death. Biological Reviews 96 (6): 2489-2521.
Johnson, D., Lardy, H. (1967). Isolation of liver or kidney mitochondria. Methods in Emzymology 10: 94–96.
Kantrow, S.P., Piantadosi, C.A. (1997). Release of cytochrome c from liver mitochondria during permeability transition. Biochem. Biophys. Res. Commun, 232: 669–671.
Kim, H.E., X. Jiang, X., F. Du, F.,and X. Wang, X. (2008) “PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1,” Molecular Cell, 30(2):239–247, 2008.
Köhler, C., Gahm, A., Noma, T., Nakazawa, A., Orrenius, S., Zhivotovsky, B. (1999). “Release of adenylate kinase 2 from the mitochondrial intermembrane space during apoptosis,” FEBS Letters, 447(1): 10–12.
Kroemer, G., Galluzzi, L., Brenner, C. (2007) Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87: 99–163.
Lapidus, R.G., Sokolove, P.M. (1993). Inhibition by spermine of the inner membrane permeability transition of isolated heart mitochondria. FEBS. Letters, 3: 314–318.
Lillie, R.D., Fulman, H.M. (1967). Histopathological Technique and Practical Histopathology. The Blauiston Division, New York and London, Acad Sci, 111: 789-792.
Lisa Marroquin, Rachel Swiss, Yvonne Will. (2014) Identifying Compounds that Induce Opening of the Mitochondrial Permeability Transition Pore in Isolated Rat Liver Mitochondria. Current Protocols in Toxicology 25 (4):1-17.
Lowry, O. H., Rosenbrough, N. J., Farr, A. L., Randall, R. J. (1951). Protein measurement with Folin phenol reagent. Journal of Biological Chemistry, 1951(193):265–27.
Martins, K.R. (2006). Targeting apoptosis with dietary bioactive agents. Minireview, 117-130 membrane lipid peroxidation in human cancer (Spain); Cancer causes and Control ;15:707-719.
Massimo Bonora, Simone Patergnani , Daniela Ramaccini, Giampaolo Morciano, Gaia Pedriali, Asrat Endrias Kahsay, Esmaa Bouhamida, Carlotta Giorgi, Mariusz R. Wieckowski, Paolo Pinton. (2020). Review Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology, Biomolecules, 10: 998.
Newmeyer, D.D., Farschon, D.M., Reed,J.C. (1994). “Cell-free apoptosis in Xenopus egg extracts: inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria,” Cell, 79, (2): 353–364.
Olorunsogo, O. O., Malomo, S.O. (1985). Sensitivity of Oligomycin-inhibited respiration of isolated rat liver mitochondria to perfluidone, a fluorinated arylalkylsulfonamide. Toxicology, 35(3): 231–240.
Olorunsogo, O., Bababunmi, E., Bassir, O. (1979) Uncoupling effects of N phosphonomethylglycine on rat liver mitochondria. Biochem Pharm. 27: 925-927.
Olowofolahan, A.O., Akanji, B.A., Olorunsogo, O.O. (2020). 3-(Para-fluorobenzoyl)-propionic acid; a metabolite of haloperidol reversed oestradiol valerate-induced uterine hyperplasia via modulation of estrogen receptor signaling pathway in female Wistar rats. Journal of Basic and Clinical Physiology and Pharmacology. Vol. 31(4).
Olowofolahan, A.O., Paulinus, O.B., Dare, H.M., Olorunsogo, O.O. (2021). Metformin induces apoptosis via uterus mitochondrial permeability transition pore opening and protects against estradiol benzoate-induced uterine defect and associated pathophysiological disorder in female Wistar rats. Bulletin of the National Research Centre. Vol. 45:102.
Paget, G. E., Barnes, J. M. (1969). Evaluation of drug activity: Pharmacometrics. In: Laurence D. R., Bacharacha A. L., ed. New york: Academic Press.
Panda, S., El khader, I., Casellas, F., Lopez Vivancos, J., GarciaCors, M., Santiago, A., Cuenca, S., Guarner, F., Manichah, C. (2014). Short term effect of Antibiotics on human Gut Microbiota. PLOA ONE. 4 (9).
Salvador-Gallego, R., Mund, M., Cosentino, K., Schneider, J., Unsay, J., Schraermeyer, U., Engelhardt, J., Ries, J., Garcia-Saez, A.J. (2016) Bax assembly into rings and arcs in apoptotic mitochondria is linked to membrane pores. EMBO J., 35: 389–401.
Schwabe, R.F., Luedde, T. (2018). “Apoptosis and necroptosis in the liver: a matter of life and death,” Nature Reviews Gastroenterology & Hepatology. 15 (12): 738–752.
Suliman, H.B., Piantadosi, C.A. (2016). “Mitochondrial quality control as a therapeutic target,” Pharmacological Reviews, 68 (1): 20–48.
Varshney, R., Kale R.K. (1990). Effect of calmodulin antagonists on radiation induced lipid peroxidation in microsomes. Int J Radiat Biol, 58:733–743.
Wu, B., Ootani, A., Iwakiri, R., Sakata, Y., Fujise, T., Amemori, S., Yokoyama, F., Tsunada, S., Toda, S., Fujimoto, K. (2006). T cell deficiency leads to liver carcinogenesis in azoxymethanetreated rats. Experimental Biology and Medicine, 231: 91–98.
Yuan Gao, Qingyao Shang, Wenyu Li, Wenxuan Guo, Alexander Stojadinovic, Ciaran Mannion, Yan-gao Man, Tingtao, Chen. (2020). Antibiotics for cancer treatment: A double-edged sword. Journal of Cancer, 11(17): 5135-5149.
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