Mitochondrial pathway‑mediated apoptosis is associated with erlotinib‑induced cytotoxicity in hepatic cells

Chen,Xueqin; Yang,Shaoyu; Pan,Yuelong; Li,Xin; Ma,Shenglin

doi:10.3892/ol.2017.7359

Mitochondrial pathway‑mediated apoptosis is associated with erlotinib‑induced cytotoxicity in hepatic cells

Authors:
- Xueqin Chen
- Shaoyu Yang
- Yuelong Pan
- Xin Li
- Shenglin Ma
View Affiliations

Affiliations: Department of Medical Oncology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China
Published online on: November 8, 2017 https://doi.org/10.3892/ol.2017.7359
Pages: 783-788
Copyright: © Chen 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

For advanced non‑small‑cell lung cancer (NSCLC) with mutations to the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors, including erlotinib are indicated for the first‑line treatment. Liver injury is one of the multiple adverse effects of erlotinib and may affect its safety. The present study investigated the mechanism of erlotinib‑induced hepatotoxicity in vitro and provided experimental evidence for the screening of potential hepatoprotectors. Erlotinib induced dose‑dependent cytotoxicity in human L‑02 hepatic cells 72 h after treatment. In other experiments, L‑02 cells were treated with erlotinib for 48 h and thereafter exhibited typical features of apoptosis. Erlotinib caused alterations to nuclear morphology, including chromatin condensation and karyopyknosis; it also increased the fraction of late apoptotic cells and regulated apoptotic protein levels, activating caspase‑3 and cleaving of poly‑ADP‑ribose polymerase. Furthermore, 48 h exposure to erlotinib disturbed mitochondrial function by decreasing the ratio of B‑cell lymphoma 2 (Bcl‑2) to Bcl‑associated X proteins and reducing mitochondrial membrane potential. The results of this in vitro study indicate that erlotinib‑induced hepatotoxicity may occur through mitochondrial‑pathway‑mediated apoptosis.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
2	Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, et al: SEER cancer statistics review 1975–2012. Natl Cancer Inst. Nov 18–2015.
3	Iranzo V, Bremnes RM, Almendros P, Gavilá J, Blasco A, Sirera R and Camps C: Induction chemotherapy followed by concurrent chemoradiation for patients with non-operable stage III non-small-cell lung cancer. Lung Cancer. 63:63–67. 2009. View Article : Google Scholar : PubMed/NCBI
4	Ozkaya S, Findik S, Dirican A and Atici AG: Long-term survival rates of patients with stage IIIB and IV non-small cell lung cancer treated with cisplatin plus vinorelbine or gemcitabine. Exp Ther Med. 4:1035–1038. 2012. View Article : Google Scholar : PubMed/NCBI
5	Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomized, phase 3 study. Lancet oncol. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI
6	Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, et al: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomized phase 3 trial. Lancet Oncol. 13:239–246. 2012. View Article : Google Scholar : PubMed/NCBI
7	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
8	Leanza L, Henry B, Sassi N, Zoratti M, Chandy KG, Gulbins E and Szabò I: Inhibitors of mitochondrial Kv1. 3 channels induce Bax/Bak-independent death of cancer cells. EMBO Mol Med. 4:577–593. 2012. View Article : Google Scholar : PubMed/NCBI
9	Russmann S, Jetter A and Kullak-Ublick GA: Pharmacogenetics of drug-induced liver injury. Hepatology. 52:748–761. 2010. View Article : Google Scholar : PubMed/NCBI
10	Teo YL, Ho HK and Chan A: Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: A meta-analysis. Cancer Treat Rev. 39:199–206. 2013. View Article : Google Scholar : PubMed/NCBI
11	Zhao S, Li H, Jiang C, Ma T, Wu C, Huo Q and Liu H: 17-Demethoxy-reblastatin, an Hsp90 inhibitor, induces mitochondria-mediated apoptosis through downregulation of Mcl-1 in human hepatocellular carcinoma cells. J Bioenerg Biomembr. 47:373–381. 2015. View Article : Google Scholar : PubMed/NCBI
12	Zhang Y, Zhou ZW, Jin H, Hu C, He ZX, Yu ZL, Ko KM, Yang T, Zhang X, Pan SY and Zhou SF: Schisandrin B inhibits cell growth and induces cellular apoptosis and autophagy in mouse hepatocytes and macrophages: Implications for its hepatotoxicity. Drug Des Devel Ther. 9:2001–2027. 2015.PubMed/NCBI
13	Chen L, Zhang F, Kong D, Zhu X, Chen W, Wang A and Zheng S: Saikosaponin D disrupts platelet-derived growth factor-β receptor/p38 pathway leading to mitochondrial apoptosis in human LO2 hepatocyte cells: A potential mechanism of hepatotoxicity. Chem Biol Interact. 206:76–82. 2013. View Article : Google Scholar : PubMed/NCBI
14	Oliver FJ, de la Rubia G, Rolli V, Ruiz-Ruiz MC, de Murcia G and Murcia JM: Importance of poly(ADP-ribose) polymerase and its cleavage in apoptosis. Lesson from an uncleavable mutant. J Biol Chem. 273:33533–33539. 1998. View Article : Google Scholar : PubMed/NCBI
15	Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T and Mocarski ES: RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature. 471:368–372. 2011. View Article : Google Scholar : PubMed/NCBI
16	Guha M, Maity P, Choubey V, Mitra K, Reiter RJ and Bandyopadhyay U: Melatonin inhibits free radical-mediated mitochondrial-dependent hepatocyte apoptosis and liver damage induced during malarial infection. J Pineal Res. 43:372–381. 2007. View Article : Google Scholar : PubMed/NCBI
17	Zhang F, Chen L, Jin H, Shao J, Wu L, Lu Y and Zheng S: Activation of Fas death receptor pathway and Bid in hepatocytes is involved in saikosaponin D induction of hepatotoxicity. Environ Toxicol Pharmacol. 41:8–13. 2016. View Article : Google Scholar : PubMed/NCBI
18	Lee WM: Etiologies of acute liver failure. Semin Liver Dis. 28:142–152. 2008. View Article : Google Scholar : PubMed/NCBI
19	McGill MR and Jaeschke H: Mechanistic biomarkers in acetaminophen-induced hepatotoxicity and acute liver failure: From preclinical models to patients. Expert Opin Drug Metab Toxicol. 10:1005–1017. 2014. View Article : Google Scholar : PubMed/NCBI
20	Williams CD, McGill MR, Farhood A and Jaeschke H: Fas receptor-deficient lpr mice are protected against acetaminophen hepatotoxicity due to higher glutathione synthesis and enhanced detoxification of oxidant stress. Food Chem Toxicol. 58:228–235. 2013. View Article : Google Scholar : PubMed/NCBI
21	McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC and Jaeschke H: The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest. 122:1574–1583. 2012. View Article : Google Scholar : PubMed/NCBI
22	Hu J, Ramshesh VK, McGill MR, Jaeschke H and Lemasters JJ: Low dose acetaminophen induces reversible mitochondrial dysfunction associated with transient c-Jun N-terminal kinase activation in mouse liver. Toxicol Sci. 150:204–15. 2016. View Article : Google Scholar : PubMed/NCBI
23	Chen X, Yang S and Ma S: Drug induced hepatotoxicity in targeted therapy for lung cancer. Zhongguo Fei Ai Za Zhi. 17:685–688. 2014.(In Chinese). PubMed/NCBI
24	Xue T, Luo P, Zhu H, Zhao Y, Wu H, Gai R, Wu Y, Yang B, Yang X and He Q: Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes. Toxicol Appl Pharmacol. 261:280–291. 2012. View Article : Google Scholar : PubMed/NCBI
25	Yang X, Wang J, Dai J, Shao J, Ma J, Chen C, Ma S, He Q, Luo P and Yang B: Autophagy protects against dasatinib-induced hepatotoxicity via p38 signaling. Oncotarget. 6:6203–6217. 2015. View Article : Google Scholar : PubMed/NCBI