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Suramin Inhibits Cell Proliferation in Ovarian and Cervical Cancer By Li et al. Cancer Cell International (2015) 15:52 DOI 10.1186/s12935-015-0196-y PRIMARY RESEARCH Open Access Suramin inhibits cell proliferation in ovarian and cervical cancer by downregulating heparanase expression HuaPing Li1, HuaLi Li2, HongJie Qu3, MingZhu Zhao1, Bo Yuan3, MingHua Cao1 and JinQuan Cui3* Abstract Background: Aberrant expression of heparanase (Hpa) is associated with apoor prognosis in ovarian and cervical cancer patients. Inhibitors of Hpa can prevent the growth and metastasis of malignant tumor cells, and suramin may be such a compound that has strong anti-proliferative effects on several kinds of cancer cells. We have therefore tested whether the growth inhibiting effect of suramin on ovarian and cervical cancer cells is due to downregulation of Hpa expression. Results: Suramin at 300–600 μg/ml significantly inhibited HO-8910 PM and HeLa cell growth at 24 h, in both a time-dependent and dose-dependent manner, with an IC50 of 320 μg/ml and 475 μg/ml, respectively. Suramin at 300 μg/ml significantly decreased the expression of Hpa mRNA (P < 0.005) and protein (P < 0.005) in both HO-8910 PM and HeLa cells at 48 h. Conclusions: The inhibitory effect of suramin on Hpa enzyme may be due to downregulating of its expression in cancer cells. These findings confirm the importance of Hpa in tumor growth and the potential clinical application of Hpa inhibitors in the treatment of ovarian and cervical cancer. Keywords: Suramin, Inhibition, Heparanase, Ovarian cancer, Cervical cancer Background no truly effective second and third line therapeutic regi- Ovarian cancer is the fifth most common cause of can- mens are in place. Therefore, new strategies are needed to cer death among females and ranks as the first cause of improve survival and enhance responsiveness to cytotoxic death in gynecologic malignancies. Due to no effective drugs. Molecular target treatment is more effective in early detection methods, ~70% ovarian cancers are often most cancers, and is now widely used. Several clinical tri- diagnosed at advanced stage. With the introduction of als of molecular target treatment have demonstrated their new treatment modalities, clinical results have been effectiveness in ovarian and cervical cancer [2-7]. But significantly improved, but the ovarian cancer 5-year some pitfalls should not be ignored, especially relating to survival rate is only 44% [1]. Uterine cervical cancer is the problem of resistance that is a major challenge facing another major healthcare concern worldwide, especially clinicians. There is the need to develop a second-line in the less developed countries. Despite advances in treatment strategy for the increasing number of patients screening, vaccination and treatment of early stage dis- who become resistance to the molecular agents. ease, advanced stage tumour, its recurrence and distant Hpa is an endo-β-glucuronidase that cleaves heparan metastasis are the main causes of treatment failure and sulfate proteoglycans within the extracellular matrix, death. Although systemic chemotherapy or radiochemo- basement membrane or on the cellular surface, directly therapy remains the standard treatment for those patients, or indirectly enhancing cell invasion, migration, and their responses to cytotoxic drugs are not satisfactory, and intravasation and extravasation, by releasing various growth factors from heparin-binding [8-10]. Overexpres- * Correspondence: [email protected] sion of Hpa in tumor cells markedly enhances their 3Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Zhengzhou University, Longitude eighth Road, Zhengzhou, China growth, angiogenesis, and metastasis [11]. Ovarian and Full list of author information is available at the end of the article cervical carcinomas express higher levels of Hpa mRNA © 2015 Li et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Li et al. Cancer Cell International (2015) 15:52 Page 2 of 11 and protein, which is associated with tumor stage at high human ovarian and cervical cancer cells. We found that grade and advanced stage [12-14]. Davidson et al. [15] suramin significantly downregulates Hpa expression in reported that the expression of Hpa in ovarian cancer is its inhibitory effect on the growth of cancer cells. 53% and 90% at the cell membrane and cytoplasm, re- spectively. Membrane expression in >5% of tumor cells Results correlates with a shorter overall survival. Immunohisto- Changes of cell morphology in HO-8910 PM cells and chemical positivity for heparanase was 63.3% (38/60) in HeLa cells after suramin treatment cervical cancer patients [14]. Hpa expression is also an Changes of cell morphology in HO-8910 PM cells and independent predictor of poor overall survival, suggest- HeLa cells were explored as part of its dose–response ing it is involved in tumor metastasis of female genital and time–response effects. Clear changes were observed tract malignancies [16]. Interestingly, elevated serum 48 and 96 h post-treatment. Cell density and non- Hpa levels correlate with malignant invasion and progres- adhesiveness of cells began to decrease and dispersion sion in ovarian cancer [17], which may facilitate disease into single cells increased after 50 μg/ml suramin treat- diagnosis and treatment surveillances. Hpa inhibitor has ment within 48 h. Membrane blebbing and increased strong anti-proliferation activity in vitro against two hu- cytoplasmic volume occurred, and viable cells markedly man ovarian cell lines, OVSAHO and SKOV-3 [18], and decreased, with dead cells floating and clumping up, in may be one of the potential tumor molecular target thera- 300 μg/ml suramin within 96 h, suggesting that HO- peutics. A potent Hpa inhibitor, PI-88 (a Phase I/II trials 8910 PM cells and HeLa cells were undergoing apoptosis product), is effective in several types of tumor [19,20]. (Figure 1b). Hpa could lead to a new therapeutic strategy for patients with advanced female genital tract malignancies. Growth changes in HO-8910P and Hela cells after suramin Suramin (8,8′-carbonyl-bis [imino-3,1-phenylenecarbo- treatment nylimino (4-methyl-3,1- phenylene) carbonylimino] bis- The growth of the HO-8910 PM and Hela cells using 1,3,5-naphthalene-trisulfonic acid) was originally used to the MTT assay showed that different doses of suramin sig- treat African parasitic infections, such as Rhodesian and nificantly inhibited growth rate from 24 to 96 (Figure 2a). Gambian trypanosomiasis. Due to its anti-proliferative ac- Inhibition with 600 μg/ml suramin at 96 h reached 70.9% tivity against several human tumor cell lines in dose- and in HO-8910 PM cells and 59.5% in Hela cells. Except for time-dependent fashion [21], suramin alone or combined the 50 μ g/ml group vs 100 μ g/ml group, inhibition of the with cytotoxic drugs has been studies in many clinical other groups of HO-8910 PM cells showed significant dif- trials that include ovarian cancer [22,23]. The anti- ferences (Ftime = 38.128, Ptime = 0.0001,Fdose = 44.984, proliferative mechanism of suramin is still not fully Pdose = 0.0001). For HeLa cells, except for 50 μg/ml understood, but its activity may be due to it inhibiting group vs 100 μg/ml, and vs 200 μg/ml group, inhibition the binding of growth factors to their receptors and dis- of the other groups was significantly different (Ftime = sociating receptor-bound growth factors, consequently 20.548, Ptime = 0.0001,Fdose = 32.324, Pdose = 0.0001). resulting in loss of signal transduction [24]. Suramin is The IC50 values of HO-8910 PM and HeLa were also considered a potent inhibitor of several nuclear 319 μg/ml, 476 μg/ml, respectively (Figure 2b).Plasma enzymes in vitro, including DNA primase, DNA poly- concentration of ≥350 μg/ml suramin led to a dose- merase α,RNApolymerase,DNAtopoisomeraseII,and limiting neurotoxicity [30] . At 96 h, treatment with reverse transcriptase, which may be important to its 200 and 300 μg/ml suramin inhibited 35.1- 43.7% of cytotoxic activity. Suramin and suramin analogues has HO-8910 PM cell growth and 22.4-31.7% of Hela cell also been shown to inhibit Hpa in many human cancer growth, confirming the toxic nature of suramin. Flow cell line by independent groups [25-28]. Suramin in- cytometry was used to detect apoptosis rate in HeLa hibits local tumor invasion and distant metastasis by cells (Figure 2c).The level in cells given 300 μg/ml both a direct and an indirect effect on cell adhesion and suramin for 48 h was significantly lower than in un- migration. New suramin analogues have now been de- treated cells (300 μg/ml group12.91 ± 1.17%vs UCG veloped to try to improve this antitumor activity and 5.01 ± 1.07%,p =0.001). overcome its side-effects [29]. Although suramin significantly inhibits the growth of Suramin inhibits HO-8910 PM and Hela cell proliferation ovarian cancer and is used in clinical trials, its anti- Proliferation of HO-8910 PM and HeLa cells treated proliferative effect is not properly understood. Indeed, with suramin showed time-dependency and dose–de- this lack of knowledge of the drug’s primary mechanism pendency. With increasing of dose and time, prolifera- of action has prevented use of suramin in female genital tion gradually decreased until 96 h. OD values of tract malignancies. Accordingly, our study has focused different groups (24, 48, 72 and 96 h) and 7 different on the in vitro cytotoxic activity of suramin against doses(50,100,200,300,400,500,600 μg/ml)were significantly Li et al.
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