Targeting glucose metabolism in chondrosarcoma cells enhances the sensitivity to doxorubicin through the inhibition of lactate dehydrogenase-A

Hua,Guojun; Liu,Yunpeng; Li,Xiangyong; Xu,Peirong; Luo,Yuchun

doi:10.3892/or.2014.3156

Targeting glucose metabolism in chondrosarcoma cells enhances the sensitivity to doxorubicin through the inhibition of lactate dehydrogenase-A

Authors:
- Guojun Hua
- Yunpeng Liu
- Xiangyong Li
- Peirong Xu
- Yuchun Luo
View Affiliations

Affiliations: Department of Orthopaedics, The 101st Hospital of the People's Liberation Army, Wuxi, Jiangsu 214044, P.R. China, Department of Hematology and Oncology, The 101st Hospital of the People's Liberation Army, Wuxi, Jiangsu 214044, P.R. China
Published online on: April 24, 2014 https://doi.org/10.3892/or.2014.3156
Pages: 2727-2734

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

Chondrosarcoma is a malignant cartilage-forming cancer composed of cells derived from transformed cells that produce cartilage. Conventional chemotherapy and radiotherapy have very limited efficacy in patients with advanced chondrosarcoma. In the present study, we reported a novel therapeutic approach in the treatment of chondrosarcoma cells. We detected that lactate dehydrogenase-A (LDHA) is highly active in chondrosarcoma cells and chondrosarcoma patient samples compared with normal chondrocyte cell lines and primary human chondrocyte. Moreover, chondrosarcoma cells exhibited elevated levels of LDHA expression under doxorubicin treatment. To further explore the mechanisms, we generated doxorubicin-resistant cells from SW1353 chondrosarcoma cell line. Notably, the activity and expression of LDHA are upregulated in doxorubicin-resistant cells. Moreover, our data showed a strong correlation between glucose metabolism and doxorubicin resistance in chondrosarcoma cells; doxorubicin-resistant cells displayed highly activated glucose metabolism and depended more on glucose supply. Finally, we reported a synergistic effect produced by incorporating doxorubicin with glycolysis inhibitors-oxamate in the combined treatment of chondrosarcoma cells in vitro and in vivo. In summary, the present study may aid in the development of new approaches using the combination of chemotherapeutic agents for the treatment of chondrosarcoma patients.

View Figures

View References

1	Gelderblom H, Hogendoorn PC, Dijkstra SD, van Rijswijk CS, Krol AD, Taminiau AH and Bovée JV: The clinical approach towards chondrosarcoma. Oncologist. 13:320–329. 2008. View Article : Google Scholar : PubMed/NCBI
2	Fiorenza F, Abudu A, Grimer RJ, Carter SR, Tillman RM, Ayoub K, Mangham DC and Davies AM: Risk factors for survival and local control in chondrosarcoma of bone. J Bone Joint Surg Br. 84:93–99. 2002. View Article : Google Scholar : PubMed/NCBI
3	Italiano A, Mir O, Cioffi A, Palmerini E, Piperno-Neumann S, Perrin C, Chaigneau L, Penel N, Duffaud F, Kurtz JE, Collard O, Bertucci F, Bompas E, Le Cesne A, Maki RG, Ray Coquard I and Blay JY: Advanced chondrosarcomas: role of chemotherapy and survival. Ann Oncol. 24:2916–2922. 2013. View Article : Google Scholar : PubMed/NCBI
4	Onishi AC, Hincker AM and Lee FY: Surmounting chemotherapy and radioresistance in chondrosarcoma: molecular mechanisms and therapeutic targets. Sarcoma. 2011:3815642011. View Article : Google Scholar : PubMed/NCBI
5	Perez J, Decouvelaere AV, Pointecouteau T, Pissaloux D, Michot JP, Besse A, Blay JY and Dutour A: Inhibition of chondrosarcoma growth by mTOR inhibitor in an in vivo syngeneic rat model. PLoS One. 7:e324582012. View Article : Google Scholar : PubMed/NCBI
6	Wang S, Konorev EA, Kotamraju S, Joseph J, Kalivendi S and Kalyanaraman B: Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms: intermediacy of H₂O₂- and p53-dependent pathways. J Biol Chem. 279:25535–25543. 2004. View Article : Google Scholar : PubMed/NCBI
7	Finn NA, Findley HW and Kemp ML: A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity. PLoS Comput Biol. 7:e10021512011. View Article : Google Scholar : PubMed/NCBI
8	Gilliam LA, Moylan JS, Patterson EW, Smith JD, Wilson AS, Rabbani Z and Reid MB: Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes. Am J Physiol Cell Physiol. 302:C195–C202. 2012. View Article : Google Scholar : PubMed/NCBI
9	Efferth T, Giaisi M, Merling A, Krammer PH and Li-Weber M: Artesunate induces ROS-mediated apoptosis in doxorubicin-resistant T leukemia cells. PLoS One. 2:e6932007. View Article : Google Scholar : PubMed/NCBI
10	Zhang J, Zhou F, Wu X, Zhang X, Chen Y, Zha BS, Niu F, Lu M, Hao G, Sun Y, Sun J, Peng Y and Wang G: Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2 in MCF-7/Adr cells. Br J Pharmacol. 165:120–134. 2012. View Article : Google Scholar : PubMed/NCBI
11	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009.PubMed/NCBI
12	Liu Y, Cao Y, Zhang W, Bergmeier S, Qian Y, Akbar H, Colvin R, Ding J, Tong L, Wu S, Hines J and Chen X: A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther. 11:1672–1682. 2012. View Article : Google Scholar : PubMed/NCBI
13	Cao X, Fang L, Gibbs S, Huang Y, Dai Z, Wen P, Zheng X, Sadee W and Sun D: Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia. Cancer Chemotherapy Pharmacol. 59:495–505. 2007. View Article : Google Scholar : PubMed/NCBI
14	Nakano A, Tsuji D, Miki H, Cui Q, El Sayed SM, Ikegame A, Oda A, Amou H, Nakamura S, Harada T, Fujii S, Kagawa K, Takeuchi K, Sakai A, Ozaki S, Okano K, Nakamura T, Itoh K, Matsumoto T and Abe M: Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells. PloS One. 6:e272222011. View Article : Google Scholar : PubMed/NCBI
15	Zhou GQ, Tang LL, Mao YP, Chen L, Li WF, Sun Y, Liu LZ, Li L, Lin AH and Ma J: Baseline serum lactate dehydrogenase levels for patients treated with intensity-modulated radiotherapy for nasopharyngeal carcinoma: a predictor of poor prognosis and subsequent liver metastasis. Int J Radiat Oncol Biol Phys. 82:e359–e365. 2012. View Article : Google Scholar
16	Zhou M, Zhao Y, Ding Y, Liu H, Liu Z, Fodstad O, Riker AI, Kamarajugadda S, Lu J, Owen LB, Ledoux SP and Tan M: 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
17	Van Oosterwijk JG, Herpers B, Meijer D, Briaire-de Bruijn IH, Cleton-Jansen AM, Gelderblom H, van de Water B and Bovée JV: Restoration of chemosensitivity for doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance. Ann Oncol. 23:1617–1626. 2012.PubMed/NCBI
18	Zaja R, Caminada D, Loncar J, Fent K and Smital T: Development and characterization of P-glycoprotein 1 (Pgp1, ABCB1)-mediated doxorubicin-resistant PLHC-1 hepatoma fish cell line. Toxicol Appl Pharmacol. 227:207–218. 2008. View Article : Google Scholar : PubMed/NCBI
19	Latorre E, Tebaldi T, Viero G, Spartà AM, Quattrone A and Provenzani A: Downregulation of HuR as a new mechanism of doxorubicin resistance in breast cancer cells. Mol Cancer. 11:132012. View Article : Google Scholar : PubMed/NCBI