Hepatocellular toxicity of oxalicumone A via oxidative stress injury and mitochondrial dysfunction in healthy human liver cells

Shi,Si; Yao,Limei; Guo,Kunbin; Wang,Xiangyu; Wang,Qi; Li,Weirong

doi:10.3892/mmr.2017.7979

Hepatocellular toxicity of oxalicumone A via oxidative stress injury and mitochondrial dysfunction in healthy human liver cells

Authors:
- Si Shi
- Limei Yao
- Kunbin Guo
- Xiangyu Wang
- Qi Wang
- Weirong Li
View Affiliations

Affiliations: Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China, School of Traditional Chinese Medicine Healthcare, Guangdong Food and Drug Vocational College, Guangzhou, Guangdong 510520, P.R. China
Published online on: November 6, 2017 https://doi.org/10.3892/mmr.2017.7979
Pages: 743-752
Copyright: © Shi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The marine‑derived oxalicumone A (POA) has been demonstrated as a potent anti‑tumor bioactive agent for a variety of human carcinoma, but to the best of our knowledge, remains to be evaluated in healthy liver cells. As many drugs distribute preferentially in the liver, the present study aimed to investigate the effects of POA on apoptosis, oxidative stress and mitochondrial function in L‑02 healthy liver cells. A Cell‑Counting kit‑8 assay demonstrated that POA inhibits the proliferation of L‑02 cells in a dose‑ and time‑dependent manner. Furthermore, POA induced apoptosis by increasing the percentage of cells in early apoptosis and the sub‑G1 cell cycle, along with causing S‑phase arrest in L‑02 cells. Additionally, POA activated caspase 3, increased the protein expression levels of Fas ligand and B‑cell lymphoma X‑associated protein, and decreased the expression of the anti‑apoptotic protein B‑cell lymphoma 2. POA additionally reduced the content of GSH and the activity of superoxide dismutase, elevated malondialdehyde and nitric oxide levels, increased reactive oxygen species production and the levels of alanine aminotransferase and aspartate aminotransferase, which suggested that POA induced lipid peroxidation injury in L‑02 cells and that oxidative stress serves an important role. Furthermore, POA caused alternations of mitochondrial function, including an abrupt depletion of adenosine triphosphate synthesis, mitochondrial permeability transition pore opening and depletion of mitochondrial membrane potential in L‑02 cells. These data suggested that POA exerts cytotoxicity, at least in part, by inducing oxidative stress, mitochondrial dysfunction, and eventually apoptosis. Changes in mitochondrial function and oxidative stress by POA may therefore be critical in POA‑induced toxicity in L‑02 cells.

View Figures

View References

1	Russmann S, Kullak-Ublick GA and Grattagliano I: Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 16:3041–3053. 2009. View Article : Google Scholar : PubMed/NCBI
2	Gerets HH, Tilmant K, Gerin B, Chanteux H, Depelchin BO, Dhalluin S and Atienzar FA: Characterization of primary human hepatocytes, HepG2 cells and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. Cell Biol Toxicol. 28:69–87. 2012. View Article : Google Scholar : PubMed/NCBI
3	O'Brien PJ, Irwin W, Diaz D, Howard-Cofield E, Krejsa CM, Slaughter MR, Gao B, Kaludercic N, Angeline A, Bernardi P, et al: High concordance of drug-induced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-Based model using high content screening. Arch Toxicol. 80:580–604. 2006. View Article : Google Scholar : PubMed/NCBI
4	Aggarwal BB, Sundaram C, Malani N and Ichikawa H: Curcumin: The Indian solid gold. Adv Exp Med Biol. 595:1–75. 2007. View Article : Google Scholar : PubMed/NCBI
5	Houbraken J, Frisvad JC and Samson RA: Fleming's penicillin producing strain is not Penicillium chrysogenum but P. rubens. IMA Fungus. 2:87–95. 2011. View Article : Google Scholar : PubMed/NCBI
6	Cragg GM and Newman DJ: Natural products: A continuing source of novel drug leads. Biochim Biophys Acta. 1830:3670–3695. 2013. View Article : Google Scholar : PubMed/NCBI
7	Senni K, Pereira J, Gueniche F, Delbarre-Ladrat C, Sinquin C, Ratiskol J, Godeau G, Fischer AM, Helley D and Colliec-Jouault S: Marine polysaccharides: A source of bioactive molecules for cell therapy and tissue engineering. Mar Drugs. 9:1664–1681. 2011. View Article : Google Scholar : PubMed/NCBI
8	Sun YL, Bao J, Liu KS, Zhang XY, He F, Wang YF, Nong XH and Qi SH: Cytotoxic dihydrothiophene-condensed chromones from marine-derived fungus Penicillium oxalicum. Plata Med. 79:1474–1479. 2013. View Article : Google Scholar
9	Zhang XY, Bao J, Wang GH, He F, Xu XY and Qi SH: Diversity and antimicrobial activity of culturable fungi isolated from six species of the South China Sea gorgonians. Microb Ecol. 64:617–627. 2012. View Article : Google Scholar : PubMed/NCBI
10	Cai Q, Wei J, Zhao W, Shi S, Zhang Y, Wei R, Zhang Y, Li W and Wang Q: Toxicity of Evodiae fructus on rat liver mitochondria: The role of oxidative stress and mitochondrial permeability transition. Molecules. 19:21168–21182. 2014. View Article : Google Scholar : PubMed/NCBI
11	Zhang JQ, Shen M, Zhu CC, Yu FX, Liu ZQ, Ally N, Sun SC, Li K and Liu HL: 3-Nitropropionic acid induces ovarian oxidative stress and impairs follicle in mouse. PLoS One. 9:e865892014. View Article : Google Scholar : PubMed/NCBI
12	Zhang XY, Bao J, Zhong J, Xu XY, Nong XH and Qi SH: Enhanced production of a novel cytotoxic chromone oxalicumone a by marine-derived mutant Penicillium oxalicum SCSIO 24-2. Appl Microbiol Biotechnol. 97:9657–9663. 2013. View Article : Google Scholar : PubMed/NCBI
13	Jacobson MD, Weil M and Raff MC: Programmed cell death in the animal development. Cell. 88:347–354. 1997. View Article : Google Scholar : PubMed/NCBI
14	Pirocanac EC, Nassirpour R, Yang M, Wang J, Nardin SR, Gu J, Fang B, Moossa AR, Hoffman RM and Bouvet M: Bax-induction gene therapy of pancreatic cancer. J Surg Res. 106:346–351. 2002. View Article : Google Scholar : PubMed/NCBI
15	Wilson MR: Apoptotic signal transduction: Emerging pathways. Biochem Cell Biol. 76:573–782. 1998. View Article : Google Scholar : PubMed/NCBI
16	Daniel PT, Wieder T, Sturm I and Schulze-Osthoff K: The kiss of death: Promises and failures of death receptors and ligands in cancer therapy. Leukemia. 15:1022–1032. 2001. View Article : Google Scholar : PubMed/NCBI
17	Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y and Nagata S: The polypeptide encoded by the cDNA for human cell surface antigen fas can mediate apoptosis. Cell. 66:233–243. 1991. View Article : Google Scholar : PubMed/NCBI
18	Waring P and Müllbacher A: Cell death induced by the Fas/Fas ligand pathway and its role in pathology. Immunol Cell Biol. 77:312–317. 1999. View Article : Google Scholar : PubMed/NCBI
19	Certo M, Del Gaizo V, Nishino M, Wei G, Korsmeyer S, Armstrong SA and Letai A: Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 9:351–365. 2006. View Article : Google Scholar : PubMed/NCBI
20	Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP and Wang X: Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science. 275:1129–1132. 1997. View Article : Google Scholar : PubMed/NCBI
21	Lanave C, Santamaria M and Saccone C: Comparative genomics: The evolutionary history of the Bcl-2 family. Gene. 333:71–79. 2004. View Article : Google Scholar : PubMed/NCBI
22	Hussain SM and Frazier JM: Cellular toxicity of hydrazine in primary rat hepatocytes. Toxicol Sci. 69:424–432. 2002. View Article : Google Scholar : PubMed/NCBI
23	Valko M, Jomova K, Rhodes CJ, Kuča K and Musílek K: Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol. 90:1–37. 2016. View Article : Google Scholar : PubMed/NCBI
24	Farber JL, Kyle ME and Coleman JB: Mechanisms of cell injury by activated oxygen species. Lab Invest. 62:670–679. 1990.PubMed/NCBI
25	Sinha K, Das J, Pal PB and Sil PC: Oxidative stress: The mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol. 87:1157–1180. 2013. View Article : Google Scholar : PubMed/NCBI
26	Yao J, Jiang Z, Duan W, Huang J, Zhang L, Hu L, He L, Li F, Xiao Y, Shu B and Liu C: Involvement of mitochondrial pathway in triptolide-induced cytotoxicity in human normal liver L-02 cells. Biol Pharm Bull. 31:592–597. 2008. View Article : Google Scholar : PubMed/NCBI
27	Ramachandran A, Lebofsky M, Baines CP, Lemasters JJ and Jaeschke H: Cyclophilin d deficiency protects against acetaminophen-induced oxidant stress and liver injury. Free Radic Res. 45:156–164. 2011. View Article : Google Scholar : PubMed/NCBI
28	Haasio K, Koponen A, Penttilä KE and Nissinen E: Effects of entacapone and tolcapone on mitochondrial membrane potential. Eur J Pharmacol. 453:21–26. 2002. View Article : Google Scholar : PubMed/NCBI
29	Green DR and Reed JC: Mitochondria and apoptosis. Science. 281:1309–1312. 1998. View Article : Google Scholar : PubMed/NCBI
30	Urra FA, Cordova-Delgado M, Pessoa-Mahana H, Ramirez-Rodriguez O, Weiss-Lopez B, Ferreira J and Araya-Maturana R: Mitochondria: A promising target for anticancer alkaloids. Curr Top Med Chem. 13:2171–2183. 2013. View Article : Google Scholar : PubMed/NCBI