Sulfated polysaccharide‑protein complex sensitizes doxorubicin‑induced apoptosis of breast cancer cells in vitro and in vivo

Wang,Jie; Wu,Hua Jian; Zhou,Chao Zhu; Wang,Hao

doi:10.3892/etm.2016.3574

Sulfated polysaccharide‑protein complex sensitizes doxorubicin‑induced apoptosis of breast cancer cells in vitro and in vivo

Authors:
- Jie Wang
- Hua Jian Wu
- Chao Zhu Zhou
- Hao Wang
View Affiliations

Affiliations: Department of Surgery, Hushan Hospital, Fudan University, Shanghai 200040, P.R. China, Fudan University Experimental Teaching Center of Basic Medicine, Fudan University School of Medicine, Shanghai 200040, P.R. China
Published online on: August 4, 2016 https://doi.org/10.3892/etm.2016.3574
Pages: 2169-2176

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 present study aimed to investigate the effect of sulfated polysaccharide‑protein complex (SPPC) on the antitumor effect of doxorubicin (Dox) on MDA‑MB‑231 breast cancer cells in vitro and in vivo. MTT and Annexin V/propidium iodide staining assays demonstrated that SPPC selectively sensitized MDA‑MB‑231 cells to Dox‑induced cytotoxicity. The half maximal inhibitory concentration of Dox against MDA‑MB‑231 cells was decreased from 5.3 to 1.5 µM when it was used concomitantly with 5 µM SPPC. SPPC potentiated Dox‑induced apoptosis in breast cancer cells via the mitochondrial apoptosis signaling pathway by activating caspase‑3 and caspase‑9. Notably, the caspase inhibitor Z‑VAD‑fmk diminished the effect of SPPC on Dox‑mediated apoptosis. Furthermore, combination treatment with SPPC and Dox markedly reduced the growth of breast cancer xenografts in mice. The present study demonstrated that SPPC was able to enhance the antitumor effect of Dox on breast cancer cells, thus suggesting that SPCC may be used to reduce the cumulative dose of Dox and its associated toxicities in the chemotherapy of breast cancer and other types of cancer.

View Figures

View References

1	Gabius S and Gabius HJ: Sugar receptors of the stromal cell layer in human long-term bone marrow cultures: Their presence, modulatory responses to changes in the microenvironment and potential role in cellular adhesion. Blut. 61:232–239. 1990. View Article : Google Scholar : PubMed/NCBI
2	Hanušová V, Boušová I and Skálová L: Possibilities to increase the effectiveness of doxorubicin in cancer cells killing. Drug Metab Rev. 43:540–557. 2011. View Article : Google Scholar : PubMed/NCBI
3	Harashima HI, Iida S, Urakami Y, Tsuchihashi M and Kiwada H: Optimization of antitumor effect of liposomally encapsulated doxorubicin based on simulations by pharmacokinetic/pharmacodynamic modeling. J Control Release. 61:93–106. 1999. View Article : Google Scholar : PubMed/NCBI
4	Green DR: Apoptotic pathways: Paper wraps stone blunts scissors. Cell. 102:1–4. 2000. View Article : Google Scholar : PubMed/NCBI
5	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 H(2)O(2)- and p53-dependent pathways. J Biol Chem. 279:25535–25543. 2004. View Article : Google Scholar : PubMed/NCBI
6	Singal PK and Iliskovic N: Doxorubicin-induced cardiomyopathy. N Engl J Med. 339:900–905. 1998. View Article : Google Scholar : PubMed/NCBI
7	Minotti G, Menna P, Salvatorelli E, Cairo G and Gianni L: Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 56:185–229. 2004. View Article : Google Scholar : PubMed/NCBI
8	Xiong Y, Liu X, Lee CP, Chua BH and Ho YS: Attenuation of doxorubicin-induced contractile and mitochondrial dysfunction in mouse heart by cellular glutathione peroxidase. Free Radic Biol Med. 41:46–55. 2006. View Article : Google Scholar : PubMed/NCBI
9	Nickels S, Truong T, Hein R, Stevens K, Buck K, Behrens S, Eilber U, Schmidt M, Häberle L, Vrieling A, et al: Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors. PLoS Genet. 9:e10032842013. View Article : Google Scholar : PubMed/NCBI
10	Glasziou P and Houssami N: The evidence base for breast cancer screening. Prev Med. 53:100–102. 2011. View Article : Google Scholar : PubMed/NCBI
11	Gottesman MM, Fojo T and Bates SE: Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer. 2:48–58. 2002. View Article : Google Scholar : PubMed/NCBI
12	Febriansah R, Putri DD, Sarmoko, Nurulita NA, Meiyanto E and Nugroho AE: Hesperidin as a preventive resistance agent in MCF-7 breast cancer cells line resistance to doxorubicin. Asian Pac J Trop Biomed. 4:228–233. 2014. View Article : Google Scholar : PubMed/NCBI
13	Wang S, Chen R, Zhong Z, Shi Z, Chen M and Wang Y: Epigallocatechin-3-gallate potentiates the effect of curcumin in inducing growth inhibition and apoptosis of resistant breast cancer cells. Am J Chin Med. 42:1279–1300. 2014. View Article : Google Scholar : PubMed/NCBI
14	Shirosaki M and Koyama T: Laminaria japonica as a food for the prevention of obesity and diabetes. Adv Food Nutr Res. 64:199–212. 2011. View Article : Google Scholar : PubMed/NCBI
15	Chen D, Yao WJ, Zhang XL, Han XQ, Qu XY, Ka WB, Sun DG, Wu XZ and Wen ZY: Effects of Gekko sulfated polysaccharide-protein complex on human hepatoma SMMC-7721 cells: Inhibition of proliferation and migration. J Ethnopharmacol. 127:702–708. 2010. View Article : Google Scholar : PubMed/NCBI
16	Chen D, Zhang X, Du Y, Jia B, Ka W, Sun D, Yao W and Wen Z: Effects of Gekko sulfated polysaccharide-protein complex on the defective biorheological characters of dendritic cells under tumor microenvironment. Cell Biochem Biophys. 62:193–201. 2012. View Article : Google Scholar : PubMed/NCBI
17	Parish CR, Coombe DR, Jakobsen KB, Bennett FA and Underwood PA: Evidence that sulphated polysaccharides inhibit tumour metastasis by blocking tumour-cell-derived heparanases. Int J Cancer. 40:511–518. 1987. View Article : Google Scholar : PubMed/NCBI
18	Parish CR, Freeman C, Brown KJ, Francis DJ and Cowden WB: Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res. 59:3433–3441. 1999.PubMed/NCBI
19	Wu XZ, Chen D and Han XQ: Anti-migration effects of Gekko sulfated glycopeptide on human hepatoma SMMC-7721 cells. Molecules. 16:4958–4970. 2011. View Article : Google Scholar : PubMed/NCBI
20	Ding XL, Man YN, Hao J, Zhu CH, Liu C, Yang X and Wu XZ: The antitumor effect of Gekko sulfated glycopeptide by inhibiting bFGF-induced lymphangiogenesis. Biomed Res Int. Apr 12–2016.(Epub ahead of print) doi: 10.1155/2016/7396392. View Article : Google Scholar
21	Atashrazm F, Lowenthal RM, Woods GM, Holloway AF and Dickinson JL: Fucoidan and cancer: A multifunctional molecule with anti-tumor potential. Mar Drugs. 13:2327–2346. 2015. View Article : Google Scholar : PubMed/NCBI
22	Nair KL, Jagadeeshan S, Nair SA and Kumar GS: Folic acid conjugated δ-valerolactone-poly(ethylene glycol) based triblock copolymer as a promising carrier for targeted doxorubicin delivery. PLoS One. 8:e706972013. View Article : Google Scholar : PubMed/NCBI
23	Zhao H, Li Y, Wang Y, Zhang J, Ouyang X, Peng R and Yang J: Antitumor and immunostimulatory activity of a polysaccharide-protein complex from Scolopendra subspinipes mutilans L. Koch in tumor-bearing mice. Food Chem Toxicol. 50:2648–2655. 2012. View Article : Google Scholar : PubMed/NCBI
24	Jafari M, MonsefEsfahani A and Solimani B: Diagnostic value of immunoperoxidase staining and immunofluorescence in the study of kidney biopsy specimens. Iran J Kidney Dis. 9:286–290. 2015.PubMed/NCBI
25	Thorburn J, Bender LM, Morgan MJ and Thorburn A: Caspase- and serine protease-dependent apoptosis by the death domain of FADD in normal epithelial cells. Mol Biol Cell. 14:67–77. 2003. View Article : Google Scholar : PubMed/NCBI
26	Fulda S and Debatin KM: Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 25:4798–4811. 2006. View Article : Google Scholar : PubMed/NCBI
27	Yang L, Wang P, Wang H, Li Q, Teng H, Liu Z, Yang W, Hou L and Zou X: Fucoidan derived from Undaria pinnatifida unduces apoptosis in human hepatocellular carcinoma SMMC-7721 cells via the ROS-mediated mitochondrial pathway. Mar Drugs. 11:1961–1976. 2013. View Article : Google Scholar : PubMed/NCBI
28	Liu G, Kuang S, Wu S, Jin W and Sun C: A novel polysaccharide from Sargassum integerrimum induces apoptosis in A549 cells and prevents angiogenesis in vitro and in vivo. Sci Rep. May 24–2016.(Epub ahead of print) doi: 10.1038/srep26722.
29	Kim JY and Park JH: ROS-dependent caspase-9 activation in hypoxic cell death. FEBS Lett. 549:94–98. 2003. View Article : Google Scholar : PubMed/NCBI
30	Diaby V, Tawk R, Sanogo V, Xiao H and Montero AJ: A review of systematic reviews of the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer. Breast Cancer Res Treat. 151:27–40. 2015. View Article : Google Scholar : PubMed/NCBI
31	Yeung TK, Chakrabarti K, Wilding D and Hopewell JW: Modification of doxorubicin-induced cardiotoxicity: Manipulation of the dosage schedule. Hum Exp Toxicol. 21:607–614. 2002. View Article : Google Scholar : PubMed/NCBI
32	Dayton A, Selvendiran K, Meduru S, Khan M, Kuppusamy ML, Naidu S, Kálai T, Hideg K and Kuppusamy P: Amelioration of doxorubicin-induced cardiotoxicity by an anticancer-antioxidant dual-function compound, HO-3867. J Pharmacol Exp Ther. 339:350–357. 2011. View Article : Google Scholar : PubMed/NCBI
33	Yu YY, Dong Q, Zhao X, Gan X, Lu Q and Xu X: SPPC: A novel inhibitor of bcr fusion gene with potent anti-leukemia activity. Zhong Yi Za Zhi. 30:17–23. 2010.
34	Wu X, Chen D and Xie GR: Effects of Gekko sulfated polysaccharide on the proliferation and differentiation of hepatic cancer cell line. Cell Biol Int. 30:659–664. 2006. View Article : Google Scholar : PubMed/NCBI
35	Zhang L, Zhang M, Zhou Q, Chen J and Zeng F: Solution properties of antitumor sulfated derivative of alpha-(1->3)-D-glucan from Ganoderma lucidum. Biosci Biotechnol Biochem. 64:2172–2178. 2000. View Article : Google Scholar : PubMed/NCBI
36	Wang GY, Lu QH, Xu RZ and Dong QH: SPPC induces apoptosis in human osteosarcoma cell line MG-63 by loss in mitochondrial transmembrane potential and caspase activation. Zhejiang Da Xue Xue Bao. 8:248–255. 2007.(In Chinese).
37	Liu J, Mao W, Ding B and Liang CS: ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes. Am J Physiol Heart Circ Physiol. 295:H1956–H1965. 2008. View Article : Google Scholar : PubMed/NCBI
38	Zigler M, Villares GJ, Lev DC, Melnikova VO and Bar-Eli M: Tumor immunotherapy in melanoma: Strategies for overcoming mechanisms of resistance and escape. Am J Clin Dermatol. 9:307–311. 2008. View Article : Google Scholar : PubMed/NCBI
39	Postescu ID, Chereches G, Tatomir C, Daicoviciu D and Filip GA: Modulation of doxorubicin-induced oxidative stress by a grape (Vitis vinifera L.) seed extract in normal and tumor cells. J Med Food. 15:639–645. 2012. View Article : Google Scholar : PubMed/NCBI
40	Hu B, Wang SS and Du Q: Traditional Chinese medicine for prevention and treatment of hepatocarcinoma: From bench to bedside. World J Hepatol. 7:1209–1232. 2015. View Article : Google Scholar : PubMed/NCBI