Topical Treatment of Skin Squamous Cell Carcinoma with Potassium Dobesilate Cream

• Pedro Cuevas

  Departamento de Investigación, Servicio de Histología, IRYCIS

• Javier Angulo

  Departamento de Investigación, Servicio de Histología, IRYCIS

• Adrián Cuevas-Bourdier

  Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal

• Guillermo Giménez-Gallego

  Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain

 Skin squamous cell carcinoma, the second most common skin cancer arises from the malignant proliferation of keratinocytes in the epidermis. Although it is locally invasive, surgical excision or topical therapy is usually curative. However, surgical management of skin squamous cell carcinoma located in certain regions of the body may require reconstructive procedures. This can result in significant scarring and increased morbidity and dysfunction. Topical therapy may be preferable to surgery depending on anatomic localizations, and in instances where patients reject it or are poor surgical candidates. Fibroblast growth factors are variously implicated in skin tumorigenesis where they may be involved in the enhancement of tumor cell proliferation and viability, induction of angiogenesis and stimulation of tumor invasiveness. We investigated the efficacy and safety of the fibroblast growth factor inhibitor, dobesilate, administered as a 5% potassium cream, for the treatment of skin squamous cell carcinoma. Two months application of dobesilate cleared squamous cell carcinoma probably due to inhibition of cell proliferation and angiogenesis, and induction of tumor cell apoptosis. No local side effects were observed in relation with treatment. This report highlights the need for efficient and safe topical therapies in the management of skin neoplasms and supports the use of potassium dobesilate in non-melanoma skin cancers treatment.

Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 2010; 146: 283-7. http://dx.doi.org/10.1001/archdermatol.2010.19

Gallagher RP, Hill GB, Bajdik CD, et al. Sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin cancer. II. Squamous cell carcinoma. Arch Dermatol 1995; 131: 164-9. http://dx.doi.org/10.1001/archderm.1995.01690140048007

Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol 1997; 36: 650-3. http://dx.doi.org/10.1016/S0190-9622(97)70265-2

Dinehart SM, Nelson-Adesokan P, Cockerell C, Russell S, Brown R. Metastatic cutaneous squamous cell carcinoma derived from actinic keratosis. Cancer 1997; 79: 920-3. http://dx.doi.org/10.1002/(SICI)1097-0142(19970301)79:5<920::AID-CNCR8>3.0.CO;2-F

Gupta AK. The management of actinic keratoses in the United States with topical fluorouracil: a pharmacoeconomic evaluation. Cutis 2002; 70 (2 Suppl): 30-6.

Hu B, Castillo E, Harewood L, et al. Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell 2012; 149: 1207-20. http://dx.doi.org/10.1016/j.cell.2012.03.048

Vanharanta S, Massagué J. Field cancerization: something new under the sun. Cell 2012; 149: 1179-81. http://dx.doi.org/10.1016/j.cell.2012.05.013

Kim HR, Heo YM, Jeong KI, et al. FGF-2 inhibits TNF-〈 mediated apoptosis through upregulation of Bcl2-A1 and Bcl-xL in ATDC5 cells. BMB Rep 2012; 45: 287-92. http://dx.doi.org/10.5483/BMBRep.2012.45.5.287

Cuevas P, Angulo J, Giménez-Gallego G. Topical treatment of contact dermatitis by pine processionary caterpillar. Brit Med J Case Reports doi: 10-1136/bcr.06.2011.4351 (Pub. 14-08-2011)

Fernández IS, Cuevas P, Angulo J, et al. Gentisic acid, a compound associated with plant defense and a metabolite of aspirin, heads a new class of in vivo fibroblast growth factor inhibitors. J Biol Chem 2010; 285: 11714-29. http://dx.doi.org/10.1074/jbc.M109.064618

Cuevas P, Espinoza W, Pérez C, Angulo J, Giménez-Gallego G. Topical treatment of actinic keratoses with potassium dobesilate 5% cream. A preliminary open-label study. Eur J Med Res 2011; 16: 67-70. http://dx.doi.org/10.1186/2047-783X-16-2-67

Cuevas P, De Miguel R, Espinoza W, et al. Antimelanoma effect of a synthetic inhibitor of fibroblast growth factor (FGF). Proceedings of the 13th World Congress on cancers of the Skin, Madrid, Spain 2011; Abst. 79

Cuevas P, Arrazola JM. Treatment of basal cell carcinoma with topical dobesilate. J Am Acad Dermatol 2005; 53: 526-7. http://dx.doi.org/10.1016/j.jaad.2005.04.014

Cuevas P, Calvo M, Angulo J, Cuevas-Bourdier A, Giménez-Gallego G. Efficacy of the fibroblast growth factor inhibitor 2,5 dihydroxyphenylsulfonate, in basal cell carcinoma: an histopahological and inmunohistochemical study. J Dermatolog Treat 2011; 22: 348-52. http://dx.doi.org/10.3109/09546634.2010.551108

Cuevas P, Angulo J, Cuevas-Bourdier A, Salgüero I, Giménez-Gallego G. Treatment of infiltrative basal cell carcinomas by inhibiting the fibroblast growth factor (FGF)-signal transducer and activator of transcription (STAT)-3 signalling pathways. J Cancer Sci Ther Doi:104172/1948-5956.S3-0032.

Freier K, Schwaenen C, Sticht C, et al. Recurrent FGFR1 amplification and high FGFR1 protein expression in oral squamous cell carcinoma (OSCC). Oral Oncol 2007; 43: 60-6. http://dx.doi.org/10.1016/j.oraloncology.2006.01.005

Ratushny V, Gober MD, Hick R, Ridky TW, Seykora JT. From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. J Clin Invest 2012; 122: 464-72. http://dx.doi.org/10.1172/JCI57415

Freier K, Schwaenen C, Sticht C, et al. Recurrent FGFR1 amplification and high FGFR1 protein expression in oral squamous cell carcinoma (OSCC). Oral Oncol 2007; 43: 60-6. http://dx.doi.org/10.1016/j.oraloncology.2006.01.005

Marek L, Ware KE, Fritzsche A, et al. Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol Pharmacol 2009; 75: 196-207. http://dx.doi.org/10.1124/mol.108.049544

Bikfalvi A, Klein S, Pintucci G, Rifkin DB. Biological roles of fibroblast growth factor-2. Endocr Rev 1997; 18: 26-45. http://dx.doi.org/10.1210/er.18.1.26

Yamazaki K, Nagao T, Yamaguchi T, Saisho H, Kondo Y. Expression of basic fibroblast growth factor (FGF-2)-associated with tumour proliferation in human pancreatic carcinoma. Virchows Arch 1997; 431: 95-101. http://dx.doi.org/10.1007/s004280050074

Giri D, Ropiquet F, Ittmann M. Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Cancer Res 1999; 5: 1063-71.

Barclay C, Li AW, Geldenhuys L, et al. Basic fibroblast growth factor (FGF-2) overexpression is a risk factor for esophageal cancer recurrence and reduced survival, which is ameliorated by coexpression of the FGF-2 antisense gene. Clin Cancer Res 2005; 11: 7683-91. http://dx.doi.org/10.1158/1078-0432.CCR-05-0771

Syed ZA, Yin W, Hughes K, Gill JN, Shi R, Clifford JL. HGF/c-met/Stat3 signaling during skin tumor cell invasion: indications for a positive feedback loop. BMC Cancer 2011; 11: 180. http://dx.doi.org/10.1186/1471-2407-11-180

Chilampalli C, Guillermo R, Zhang X, et al. Effects of magnolol on UVB-induced skin cancer development in mice and its possible mechanism of action. BMC Cancer 2011; 11: 456. http://dx.doi.org/10.1186/1471-2407-11-456

Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798-809. http://dx.doi.org/10.1038/nrc2734

Deo DD, Axelrad TW, Robert EG, Marcheselli V, Bazan NG, Hunt JD. Phosphorylation of STAT-3 in response to basic fibroblast growth factor occurs through a mechanism involving platelet-activating factor, JAK-2, and Src in human umbilical vein endothelial cells. Evidence for a dual kinase mechanism. J Biol Chem 2002; 277: 21237-45. http://dx.doi.org/10.1074/jbc.M110955200

Cuevas P, Díaz-González D, Sánchez I, Lozano RM, Giménez-Gallego G, Dujovny M. Dobesilate inhibits the activation of signal transducer and activator of transcription (Stat)3 and the expression of cyclin D1 and bcl-XL in glioma cells. Neurol Res 2006; 28: 127-30. http://dx.doi.org/10.1179/016164106X97982

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