Inhibition of steroid sulphatase activity via the percutaneous route

a new option for breast cancer therapy

A. Purohit, S. K. Chander, L. W. L. Woo, M. F. C. Parsons, R. Jhalli, B. V. L. Potter, M J Reed

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Steroid sulphatase (STS) inhibitors have been developed primarily for the treatment of hormone-dependent breast cancer, but may also have utility for the treatment of a number of androgen-dependent skin conditions. STS regulates the hydrolysis of steroid sulphates, such as oestrone sulphate (E1S) and dehydroepiandrosterone sulphate, (DHEAS). Liberated oestrone (E1) can be converted to biologically active oestradiol (E2) while dehydroepiandrosterone (DHEA) can undergo reduction to testosterone or aromatisation to E1. In this study the ability of the STS inhibitor STX64 (BN83495) and its N,N-dimethyl analogue (STX289) to inhibit liver and skin STS when applied orally or topically to nude mice was examined. Oral administration at 1 and 10 mg/kg resulted in almost complete inhibition of skin and liver STS. When applied topically to the dorsal neck region at 1.0 and 10 mg/kg not only skin but, unexpectedly, also liver STS was effectively inhibited. An investigation into the metabolism of these two compounds by HepG2 liver carcinoma cells, with high-performance liquid chromatography (HPLC) analysis, was also undertaken. In the presence of HepG2 cells a similar degree of desulphamoylation of STX64 (68%) or de-N, N-dimethylsulphamoylation of STX289 (66%) occurred over a 3h period. In the absence of cells, however, STX289 was resistant to de-N, N-dimethylsulphamoylation whereas STX64 was completely desulphamoylated, demonstrating the more favourable pharmaceutical profile of STX289 for development for topical application. It is concluded that both STX64 and STX289 are not only effective inhibitors of skin STS, but also liver STS when applied topically. These findings suggest that it may be possible to develop a formulation for the percutaneous administration of STS inhibitors, but also that this class of compound may have therapeutic potential for the treatment of a number of skin disorders.
Original languageEnglish
Pages (from-to)1517-1523
JournalAnticancer Research
Volume28
Issue number3A
Publication statusPublished - 2008

Fingerprint

Steryl-Sulfatase
Breast Neoplasms
Skin
Therapeutics
Liver
Cutaneous Administration
Dehydroepiandrosterone Sulfate
Dehydroepiandrosterone
Estrone
Hep G2 Cells
Nude Mice
Androgens
Sulfates
Oral Administration
Testosterone
Hepatocellular Carcinoma
Estradiol
Hydrolysis
Neck
Steroids

Keywords

  • breast cancer
  • hirsutism
  • androgen
  • oestrogen
  • sulphatase inhibitor
  • acne
  • skin
  • steroid sulphatase

Cite this

Purohit, A., Chander, S. K., Woo, L. W. L., Parsons, M. F. C., Jhalli, R., Potter, B. V. L., & Reed, M. J. (2008). Inhibition of steroid sulphatase activity via the percutaneous route: a new option for breast cancer therapy. Anticancer Research, 28(3A), 1517-1523.

Inhibition of steroid sulphatase activity via the percutaneous route : a new option for breast cancer therapy. / Purohit, A.; Chander, S. K.; Woo, L. W. L.; Parsons, M. F. C.; Jhalli, R.; Potter, B. V. L.; Reed, M J.

In: Anticancer Research, Vol. 28, No. 3A, 2008, p. 1517-1523.

Research output: Contribution to journalArticle

Purohit, A, Chander, SK, Woo, LWL, Parsons, MFC, Jhalli, R, Potter, BVL & Reed, MJ 2008, 'Inhibition of steroid sulphatase activity via the percutaneous route: a new option for breast cancer therapy', Anticancer Research, vol. 28, no. 3A, pp. 1517-1523.
Purohit, A. ; Chander, S. K. ; Woo, L. W. L. ; Parsons, M. F. C. ; Jhalli, R. ; Potter, B. V. L. ; Reed, M J. / Inhibition of steroid sulphatase activity via the percutaneous route : a new option for breast cancer therapy. In: Anticancer Research. 2008 ; Vol. 28, No. 3A. pp. 1517-1523.
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abstract = "Steroid sulphatase (STS) inhibitors have been developed primarily for the treatment of hormone-dependent breast cancer, but may also have utility for the treatment of a number of androgen-dependent skin conditions. STS regulates the hydrolysis of steroid sulphates, such as oestrone sulphate (E1S) and dehydroepiandrosterone sulphate, (DHEAS). Liberated oestrone (E1) can be converted to biologically active oestradiol (E2) while dehydroepiandrosterone (DHEA) can undergo reduction to testosterone or aromatisation to E1. In this study the ability of the STS inhibitor STX64 (BN83495) and its N,N-dimethyl analogue (STX289) to inhibit liver and skin STS when applied orally or topically to nude mice was examined. Oral administration at 1 and 10 mg/kg resulted in almost complete inhibition of skin and liver STS. When applied topically to the dorsal neck region at 1.0 and 10 mg/kg not only skin but, unexpectedly, also liver STS was effectively inhibited. An investigation into the metabolism of these two compounds by HepG2 liver carcinoma cells, with high-performance liquid chromatography (HPLC) analysis, was also undertaken. In the presence of HepG2 cells a similar degree of desulphamoylation of STX64 (68{\%}) or de-N, N-dimethylsulphamoylation of STX289 (66{\%}) occurred over a 3h period. In the absence of cells, however, STX289 was resistant to de-N, N-dimethylsulphamoylation whereas STX64 was completely desulphamoylated, demonstrating the more favourable pharmaceutical profile of STX289 for development for topical application. It is concluded that both STX64 and STX289 are not only effective inhibitors of skin STS, but also liver STS when applied topically. These findings suggest that it may be possible to develop a formulation for the percutaneous administration of STS inhibitors, but also that this class of compound may have therapeutic potential for the treatment of a number of skin disorders.",
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