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Article

Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation

  • Authors:
    • Xu‑Qin Feng
    • Li‑Wen Rong
    • Rui‑Xue Wang
    • Xue‑Lian Zheng
    • Lei Zhang
    • Lin Zhang
    • Yong Lin
    • Xia Wang
    • Zhi‑Ping Li
  • View Affiliations / Copyright

    Affiliations: Department of Abdomen Oncology, Cancer Center of West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Laboratory of Molecular and Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) of Ministry of Education, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
  • Pages: 648-653
    |
    Published online on: May 4, 2018
       https://doi.org/10.3892/ol.2018.8640
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Abstract

Sorafenib is a small‑molecule multi‑kinase inhibitor approved by FDA as an oral agent for the treatment of hepatocellular carcinoma (HCC) and renal cell carcinoma. However, unresponsiveness and acquired resistance are commonly observed, which hinder the clinical use of sorafenib. As combination therapy is a promising approach to improve its efficacy, we investigated if sorafenib and luteolin combination is effective in killing human HCC cells. Cell death was examined by lactate dehydrogenase (LDH) releasing assay. Apoptosis was detected by flow cytometric. The activation of apoptotic pathway and c‑Jun N‑terminal kinase (JNK) signaling pathway was measured by western blot. The results showed that sorafenib and luteolin combination synergistically induced cytotoxicity in HCC cells, which was accompanied by potentiation of apoptosis as demonstrated by increased apoptotic cell populations, caspase activation, and suppression of cell death by the pan‑caspase inhibitor z‑VAD‑fmk. Furthermore, the combination of both agents enhanced expression of phosphorylated form of JNK, and the JNK inhibitor SP600125 effectively attenuated cell death induced by the combination treatment. Thus, sorafenib and luteolin combination synergistically kills HCC cells through JNK‑mediated apoptosis, and luteolin may be an ideal candidate for increasing the activity of sorafenib in HCC therapy.
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1 

Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R and Kelley S: Discovery and development of sorafenib: A multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 5:835–844. 2006. View Article : Google Scholar : PubMed/NCBI

2 

Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M and Carter C: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66:11851–11858. 2006. View Article : Google Scholar : PubMed/NCBI

3 

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, et al: Efficacy and safety of sorafenib in patients in the asia-pacific region with advanced hepatocellular carcinoma: A phase iii randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10:25–34. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Kane RC, Farrell AT, Saber H, Tang S, Williams G, Jee JM, Liang C, Booth B, Chidambaram N, Morse D, et al: Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 12:7271–7278. 2006. View Article : Google Scholar : PubMed/NCBI

6 

Keating GM and Santoro A: Sorafenib: A review of its use in advanced hepatocellular carcinoma. Drugs. 69:223–240. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Gauthier A and Ho M: Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol Res. 43:147–154. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Birt DF, Hendrich S and Wang W: Dietary agents in cancer prevention: Flavonoids and isoflavonoids. Pharmacol Ther. 90:157–177. 2001. View Article : Google Scholar : PubMed/NCBI

9 

Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, Kandaswami C, Middleton E Jr and Lee MT: Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. Br J Pharmacol. 128:999–1010. 1999. View Article : Google Scholar : PubMed/NCBI

10 

Leung HW, Wu CH, Lin CH and Lee HZ: Luteolin induced DNA damage leading to human lung squamous carcinoma ch27 cell apoptosis. Eur J Pharmacol. 508:77–83. 2005. View Article : Google Scholar : PubMed/NCBI

11 

Bagli E, Stefaniotou M, Morbidelli L, Ziche M, Psillas K, Murphy C and Fotsis T: Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3′-kinase activity. Cancer Res. 64:7936–7946. 2004. View Article : Google Scholar : PubMed/NCBI

12 

Lin Y, Shi R, Wang X and Shen HM: Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets. 8:634–646. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Yan J, Wang Q, Zheng X, Sun H, Zhou Y, Li D, Lin Y and Wang X: Luteolin enhances tnf-related apoptosis-inducing ligand's anticancer activity in a lung cancer xenograft mouse model. Biochem Biophys Res Commun. 417:842–846. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Reipas KM, Law JH, Couto N, Islam S, Li Y, Li H, Cherkasov A, Jung K, Cheema AS, Jones SJ, et al: Luteolin is a novel p90 ribosomal S6 kinase (RSK) inhibitor that suppresses Notch4 signaling by blocking the activation of Y-box binding protein-1 (YB-1). Oncotarget. 4:329–345. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Yang MY, Wang CJ, Chen NF, Ho WH, Lu FJ and Tseng TH: Luteolin enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231 cells by blocking STAT3. Chem Biol Interact. 213:60–68. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Wang X, Ju W, Renouard J, Aden J, Belinsky SA and Lin Y: 17-allylamino-17-demethoxygeldanamycin synergistically potentiates tumor necrosis factor-induced lung cancer cell death by blocking the nuclear factor-kappab pathway. Cancer Res. 66:1089–1095. 2006. View Article : Google Scholar : PubMed/NCBI

17 

Zhao L, Wientjes MG and Au JL: Evaluation of combination chemotherapy: Integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clin Cancer Res. 10:7994–8004. 2004. View Article : Google Scholar : PubMed/NCBI

18 

Broecker-Preuss M, Müller S, Britten M, Worm K, Schmid KW, Mann K and Fuhrer D: Sorafenib inhibits intracellular signaling pathways and induces cell cycle arrest and cell death in thyroid carcinoma cells irrespective of histological origin or braf mutational status. BMC Cancer. 15:1842015. View Article : Google Scholar : PubMed/NCBI

19 

Bai L, Xu X, Wang Q, Xu S, Ju W, Wang X, Chen W, He W, Tang H and Lin Y: A superoxide-mediated mitogen-activated protein kinase phosphatase-1 degradation and c-Jun NH(2)-terminal kinase activation pathway for luteolin-induced lung cancer cytotoxicity. Mol Pharmacol. 81:549–555. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Ju W, Wang X, Shi H, Chen W, Belinsky SA and Lin Y: A critical role of luteolin-induced reactive oxygen species in blockage of tumor necrosis factor-activated nuclear factor-kappaB pathway and sensitization of apoptosis in lung cancer cells. Mol Pharmacol. 71:1381–1388. 2007. View Article : Google Scholar : PubMed/NCBI

21 

Kurosu T, Ohki M, Wu N, Kagechika H and Miura O: Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway. Cancer Res. 69:3927–3936. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Bai L, Chen W, Wang X, Ju W, Xu S and Lin Y: Attenuating smac mimetic compound 3-induced NF-kappaB activation by luteolin leads to synergistic cytotoxicity in cancer cells. J Cell Biochem. 108:1125–1131. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Attoub S, Hassan AH, Vanhoecke B, Iratni R, Takahashi T, Gaben AM, Bracke M, Awad S, John A, Kamalboor HA, et al: Inhibition of cell survival, invasion, tumor growth and histone deacetylase activity by the dietary flavonoid luteolin in human epithelioid cancer cells. Eur J Pharmacol. 651:18–25. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Wagner EF and Nebreda AR: Signal integration by jnk and p38 mapk pathways in cancer development. Nat Rev Cancer. 9:537–549. 2009. View Article : Google Scholar : PubMed/NCBI

25 

Haagenson K and Wu GS: Mitogen activated protein kinase phosphatases and cancer. Cancer Biol Ther. 9:337–340. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Choi AY, Choi JH, Yoon H, Hwang KY, Noh MH, Choe W, Yoon KS, Ha J, Yeo EJ and Kang I: Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells. Eur J Pharmacol. 668:115–126. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Ou DL, Shen YC, Yu SL, Chen KF, Yeh PY, Fan HH, Feng WC, Wang CT, Lin LI, Hsu C and Cheng AL: Induction of DNA damage-inducible gene GADD45beta contributes to sorafenib-induced apoptosis in hepatocellular carcinoma cells. Cancer Res. 70:9309–9318. 2010. View Article : Google Scholar : PubMed/NCBI

28 

Yu C, Friday BB, Lai JP, Yang L, Sarkaria J, Kay NE, Carter CA, Roberts LR, Kaufmann SH and Adjei AA: Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: Induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol Cancer Ther. 5:2378–2387. 2006. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Feng XQ, Rong LW, Wang RX, Zheng XL, Zhang L, Zhang L, Lin Y, Wang X and Li ZP: Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation. Oncol Lett 16: 648-653, 2018.
APA
Feng, X., Rong, L., Wang, R., Zheng, X., Zhang, L., Zhang, L. ... Li, Z. (2018). Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation. Oncology Letters, 16, 648-653. https://doi.org/10.3892/ol.2018.8640
MLA
Feng, X., Rong, L., Wang, R., Zheng, X., Zhang, L., Zhang, L., Lin, Y., Wang, X., Li, Z."Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation". Oncology Letters 16.1 (2018): 648-653.
Chicago
Feng, X., Rong, L., Wang, R., Zheng, X., Zhang, L., Zhang, L., Lin, Y., Wang, X., Li, Z."Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation". Oncology Letters 16, no. 1 (2018): 648-653. https://doi.org/10.3892/ol.2018.8640
Copy and paste a formatted citation
x
Spandidos Publications style
Feng XQ, Rong LW, Wang RX, Zheng XL, Zhang L, Zhang L, Lin Y, Wang X and Li ZP: Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation. Oncol Lett 16: 648-653, 2018.
APA
Feng, X., Rong, L., Wang, R., Zheng, X., Zhang, L., Zhang, L. ... Li, Z. (2018). Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation. Oncology Letters, 16, 648-653. https://doi.org/10.3892/ol.2018.8640
MLA
Feng, X., Rong, L., Wang, R., Zheng, X., Zhang, L., Zhang, L., Lin, Y., Wang, X., Li, Z."Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation". Oncology Letters 16.1 (2018): 648-653.
Chicago
Feng, X., Rong, L., Wang, R., Zheng, X., Zhang, L., Zhang, L., Lin, Y., Wang, X., Li, Z."Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation". Oncology Letters 16, no. 1 (2018): 648-653. https://doi.org/10.3892/ol.2018.8640
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