Suramin interference with transforming growth factor-β inhibition of human renal cell carcinoma in culture

Wade, Terence P.; Kasid, Attan; Stein, C. A.; LaRocca, Renato; Sargent, Eric R.; Gomella, Leonard G.; Myers, Charles E.; Linehan, W. Marston

doi:10.1016/0022-4804(92)90034-w

Cited by 23 publications

(8 citation statements)

References 12 publications

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“…In this regard, it has been reported that suramin can block the interaction of TGF-␤ with the TGF receptor and block the inhibitory effect of TGF-␤ in renal cancer cells (Wade et al, 1992). Previous results from our laboratory showed that RPTC can produce TGF-␤ and that oxidant-induced autocrine production of TGF-␤ has an inhibitory effect on RPTC proliferation (Nowak and Schnellmann, 1997).…”

Section: Discussionmentioning

confidence: 90%

“…These growth factors include epidermal growth factor (EGF), platelet-derived growth factor, fibroblast growth factor, and insulin growth factor II (Wang and Williams, 1984;Hosang, 1985;Betsholtz et al, 1986;Coffey et al, 1987). In addition, suramin blocks the interaction of transforming growth factor (TGF)-␤ with its receptor; TGF-␤ exerts a growth-inhibitory effect in many cell types, including renal epithelial cells (Wade et al, 1992;Sponsel et al, 1994;Nowak and Schnellmann, 1997).…”

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confidence: 99%

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Suramin Promotes Proliferation and Scattering of Renal Epithelial Cells

Zhuang

Schnellmann

2005

J Pharmacol Exp Ther

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Primary cultures of renal proximal tubules are known to recapitulate several early events in the process of renal regeneration following injury. In this study, we show that suramin, a polysulfonated naphthylurea, stimulates outgrowth, scattering, and proliferation of primary cultures of renal proximal tubule cells (RPTC). These responses were comparable to those produced by epidermal growth factor (EGF). However, AG-1478 [4-(3Ј-chloroanilino)-6,7-dimethoxy-quinazoline], a specific inhibitor of the EGF receptor, blocked EGF but not suramin-induced RPTC outgrowth, scattering, and proliferation. Suramin stimulated phosphorylation of Akt, a downstream kinase of phosphoinositide 3-kinase (PI3K), extracellular signaling-regulated kinase 1/2 (ERK1/2), and Src, but not the EGF receptor. Blockade of Src, but not the EGF receptor, inhibited Akt and ERK1/2 phosphorylation. Furthermore, inactivation of PI3K with LY294002 [2-(4morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] blocked suramin-induced RPTC outgrowth, scattering, and proliferation, whereas blockade of ERK1/2 had no effect. These data identify novel effects of suramin in RPTC outgrowth, scattering, and proliferation. Furthermore, suramininduced outgrowth, scattering, and proliferation of RPTC are through Src-mediated activation of the PI3K pathway but not ERK1/2 or the EGF receptor.

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Section: Discussionmentioning

confidence: 90%

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confidence: 99%

Suramin Promotes Proliferation and Scattering of Renal Epithelial Cells

Zhuang

Schnellmann

2005

J Pharmacol Exp Ther

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“…Our present data demonstrate that suramin can inhibit not only proliferation but also metastatic ability of a highly metastatic cell line of human renal cell carcinoma (SN12C-PM6). Few studies on the effects of suramin on proliferation of renal cell carcinoma [13][14][15] have been reported. Tayler et al [13] and Chang et al [14] demonstrated that suramin inhibited tumour growth in in vivo and in vitro studies.…”

Section: Discussionmentioning

confidence: 99%

“…Our results are consistent with these findings. However, Wade et al [15] showed that suramin enhanced tumor growth by inhibition of transforming growth factor-fl binding. Little is known about the effects of suramin on the metastatic ability of cancer cells [16].…”

Section: Discussionmentioning

confidence: 99%

Effects of suramin on metastatic ability, proliferation, and production of urokinase-type plasminogen activator and plasminogen activator inhibitor type 2 in human renal cell carcinoma cell line SN12C-PM6

et al. 1995

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Effects of suramin, a polysulfonated naphthylurea compound, on metastatic ability, proliferation, and production of plasminogen activators and plasminogen activator inhibitors were studied using the highly metastatic human renal cell carcinoma cell line, SN12C-PM6. After renal subscapular implantation of tumor cells in nude mice, suramin significantly inhibited metastasis of tumor cells to the lungs and liver. In vitro growth of tumour cells was inhibited by suramin in a dose-dependent manner, at relatively low doses (ID50 = 105 micrograms/ml). Plasminogen activator inhibitor type 2 (PAI-2) production by tumor cells was enhanced by suramin (100 micrograms/ml), whereas urokinase-type plasminogen activator (uPA) production was suppressed. Thus, the increase in PAI-2 and the decrease in uPA production correlated with the inhibitory effects on tumour growth and metastasis by suramin. Therefore suramin may be beneficial for the treatment of patients with an early stage of renal cancer with potential risk of metastasis.

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“…2,[15][16][17] In subsequent studies, we have found that low doses of suramin enhance the activities of paclitaxel and doxorubicin in mice that bear human prostate, lung, breast, and bladder xenograft tumors, [18][19][20][21] in the absence of increased toxicity. Subsequent phase I/II studies in human patients have indicated no or minimal adverse effects attributable to the low suramin doses, and suggest enhanced drug activity.…”

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confidence: 99%

Phase I Evaluation of Low‐Dose Suramin as Chemosensitizer of Doxorubicin in Dogs with Naturally Occurring Cancers

Kosarek

Couto

et al. 2006

Veterinary Internal Medicne

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Background:Low and nontoxic concentrations (10–50 μM) of suramin, which is a nonspecific inhibitor of multiple growth factors, including fibroblast growth factors, enhances the activities of cytotoxic chemotherapeutic agents, such as doxorubicin and paclitaxel, both in vitro and in vivo. Suramin has not been evaluated as a chemosensitizing agent in dogs with cancer. Hypothesis:Nontoxic suramin can be used safely as a chemosensitizer in dogs. Animals:Sixteen dogs of various breeds with measurable tumors were treated; 1 dog that had undergone amputation for osteosarcoma received adjuvant therapy. Methods:The dogs received 53 courses of treatment with suramin in combination with doxorubicin. The suramin dosage was 6.75 mg/kg IV 3 h before standard doxorubicin administration every 2 weeks. The pharmacokinetics and clinical efficacy were determined. Results:The pharmacokinetics of low‐dose suramin followed a 2‐compartment model with half‐lives of 2 h and 6 days. The distribution volume was a 0.34 ± 0.12 L/kg, and clearance was 1.86 ± 0.76 mL/kg/h. During the time interval that doxorubicin was present at therapeutically active concentrations (ie, from the start of infusion to 24 hours), the plasma concentrations were maintained within 20% of the target range (8–60 μM) in 72% of the treatments. The toxicity of the suramin/doxorubicin combination was mild and comparable to the toxicity expected for doxorubicin monotherapy. Objective partial responses were observed in 2 out of 16 evaluable dogs (13%). All 5 dogs that previously received doxorubicin showed improved responses to the suramin/doxorubicin combination. Conclusions and Clinical Importance: A fixed, low‐dose suramin regimen yields the desired target plasma concentrations in most dogs, and appears to enhance the activity of doxorubicin without enhancing toxicity.

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Suramin interference with transforming growth factor-β inhibition of human renal cell carcinoma in culture

Cited by 23 publications

References 12 publications

Suramin Promotes Proliferation and Scattering of Renal Epithelial Cells

Suramin Promotes Proliferation and Scattering of Renal Epithelial Cells

Effects of suramin on metastatic ability, proliferation, and production of urokinase-type plasminogen activator and plasminogen activator inhibitor type 2 in human renal cell carcinoma cell line SN12C-PM6

Phase I Evaluation of Low‐Dose Suramin as Chemosensitizer of Doxorubicin in Dogs with Naturally Occurring Cancers

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