Synergistic cytotoxicity of cisplatin and Taxol in overcoming Taxol resistance through the inhibition of LDHA in oral squamous cell carcinoma

Feng,Lin; E,Ling‑Ling; Soloveiv,Michail   Michailovich; Wang,Dong‑Sheng; Zhang,Bo; Dong,Yu  Wan; Liu,Hong‑Chen

doi:10.3892/ol.2015.2931

April-2015 Volume 9 Issue 4

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April-2015 Volume 9 Issue 4

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Article

Synergistic cytotoxicity of cisplatin and Taxol in overcoming Taxol resistance through the inhibition of LDHA in oral squamous cell carcinoma

Authors:
- Lin Feng
- Ling‑Ling E
- Michail Michailovich Soloveiv
- Dong‑Sheng Wang
- Bo Zhang
- Yu Wan Dong
- Hong‑Chen Liu
View Affiliations / Copyright

Affiliations: Institute of Stomatology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China, Oral Medical Research Center, Saint‑Petersburg Medical University, Saint‑Petersburg 197101, Russia
Pages: 1827-1832
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Published online on: February 3, 2015

https://doi.org/10.3892/ol.2015.2931
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Abstract

The development of chemoresistance in patients represents a major challenge in cancer treatment. Lactate dehydrogenase‑A (LDHA) is one of the principle isoforms of LDH that is expressed in breast tissue, controlling the conversion of pyruvate to lactate and also playing a significant role in the metabolism of glucose. The aim of this study was to identify whether LDHA was involved in oral cancer cell resistance to Taxol and whether the downregulation of LDHA, as a result of cisplatin treatment, may overcome Taxol resistance in human oral squamous cells. The OECM‑1 oral epidermal carcinoma cell line was used, which has been widely used as a model of oral cancer in previous studies. The role of LDHA in Taxol and cisplatin resistance were investigated and the synergistic cytotoxicity of cisplatin and/or Taxol in oral squamous cells was analyzed. Cell viability was analyzed by MTT assay, LDHA expression was analyzed by western blot analysis and siRNA tranfection was performed to knock down LDHA expression. The present study results showed that decreased levels of LDHA were responsible for the resistance of oral cancer cells to cisplatin (CDDP). CDDP treatments downregulated LDHA expression, and lower levels of LDHA were detected in the CDDP‑resistant oral cancer cells compared with the CDDP‑sensitive cells. By contrast, the Taxol‑resistant cancer cells showed elevated LDHA expression levels. In addition, small interfering RNA‑knockdown of LDHA sensitized the cells to Taxol, but desensitized them to CDDP treatment, while exogenous expression of LDHA sensitized the cells to CDDP, but desensitized them to Taxol. The present study also revealed the synergistic cytotoxicity of CDDP and Taxol for killing oral cancer cells through the inhibition of LDHA. This study highlights LDHA as a novel therapeutic target for overcoming Taxol resistance in oral cancer patients using the combined treatments of Taxol and CDDP.

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1	Stordal B, Pavlakis N and Davey R: A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship. Cancer Treat Rev. 33:688–703. 2007. View Article : Google Scholar : PubMed/NCBI
2	Lai D, Ho KC, Hao Y and Yang X: Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res. 71:2728–2738. 2011. View Article : Google Scholar : PubMed/NCBI
3	Gonçalves A, Braguer D, Kamath K, Martello L, Briand C, Horwitz S, Wilson L and Jordan MA: Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics. Proc Natl Acad Sci USA. 98:11737–11742. 2001. View Article : Google Scholar : PubMed/NCBI
4	Cheung CH, Wu SY, Lee TR, et al: Cancer cells acquire mitotic drug resistance properties through beta I-tubulin mutations and alterations in the expression of beta-tubulin isotypes. PLoS One. 5:e125642010. View Article : Google Scholar : PubMed/NCBI
5	Chen LP, Cai SM, Fan JX and Li ZT: PEBA regimen (cisplatin, etoposide, bleomycin, and adriamycin) in the treatment of drug-resistant choriocarcinoma. Gynecol Oncol. 56:231–234. 1995. View Article : Google Scholar : PubMed/NCBI
6	Donnenberg VS and Donnenberg AD: Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis. J Clin Pharmacol. 45:872–877. 2005. View Article : Google Scholar : PubMed/NCBI
7	Kavallaris M, Kuo DY, Burkhart CA, et al: Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. J Clin Invest. 100:1282–1293. 1997. View Article : Google Scholar : PubMed/NCBI
8	Panda D, Miller HP, Banerjee A, Ludueña RF and Wilson L: Microtubule dynamics in vitro are regulated by the tubulin isotype composition. Proc Natl Acad Sci USA. 91:11358–11362. 1994. View Article : Google Scholar : PubMed/NCBI
9	Martello LA, Verdier-Pinard P, Shen HJ, et al: Elevated levels of microtubule destabilizing factors in a Taxol-resistant/dependent A549 cell line with an alpha-tubulin mutation. Cancer Res. 63:1207–1213. 2003.PubMed/NCBI
10	Orr GA, Verdier-Pinard P, McDaid H and Horwitz SB: Mechanisms of Taxol resistance related to microtubules. Oncogene. 22:7280–7295. 2003. View Article : Google Scholar : PubMed/NCBI
11	Tan M, Jing T, Lan KH, et al: Phosphorylation on tyrosine-15 of p34(Cdc2) by ErbB2 inhibits p34(Cdc2) activation and is involved in resistance to taxol-induced apoptosis. Mol Cell. 9:993–1004. 2002. View Article : Google Scholar : PubMed/NCBI
12	Cepeda V, Fuertes MA, Castilla J, et al: Biochemical mechanisms of cisplatin cytotoxicity. Anticancer Agents Med Chem. 7:3–18. 2007. View Article : Google Scholar : PubMed/NCBI
13	Galluzzi L, Senovilla L, Vitale I, et al: Molecular mechanisms of cisplatin resistance. Oncogene. 31:1869–1883. 2012. View Article : Google Scholar
14	Hiraishi Y, Wada T, Nakatani K, et al: EGFR inhibitor enhances cisplatin sensitivity of oral squamous cell carcinoma cell lines. Pathol Oncol Res. 14:39–43. 2008. View Article : Google Scholar : PubMed/NCBI
15	Liang XJ, Finkel T, Shen DW, et al: SIRT1 contributes in part to cisplatin resistance in cancer cells by altering mitochondrial metabolism. Mol Cancer Res. 6:1499–1506. 2008. View Article : Google Scholar : PubMed/NCBI
16	Shimanishi M, Ogi K, Sogabe Y, et al: Silencing of GLUT-1 inhibits sensitization of oral cancer cells to cisplatin during hypoxia. J Oral Pathol Med. 42:382–388. 2013. View Article : Google Scholar
17	Semenza GL: Tumor metabolism: cancer cells give and take lactate. J Clin Invest. 118:3835–3837. 2008.PubMed/NCBI
18	Zhou M, Zhao Y, Ding Y, et al: Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol. Mol Cancer. 9:332010. View Article : Google Scholar : PubMed/NCBI
19	Huang GC, Liu SY, Lin MH, Kuo YY and Liu YC: The synergistic cytotoxicity of cisplatin and taxol in killing oral squamous cell carcinoma. Jpn J Clin Oncol. 34:499–504. 2004. View Article : Google Scholar : PubMed/NCBI
20	Shin YK, Yoo BC, Hong YS, et al: Upregulation of glycolytic enzymes in proteins secreted from human colon cancer cells with 5-fluorouracil resistance. Electrophoresis. 30:2182–2192. 2009. View Article : Google Scholar : PubMed/NCBI
21	Vaughn AE and Deshmukh M: Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol. 10:1477–1483. 2008. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Synergistic cytotoxicity of cisplatin and Taxol in overcoming Taxol resistance through the inhibition of LDHA in oral squamous cell carcinoma

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