Design and validation of specific inhibitors of 17beta-hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis.

نویسندگان

  • Joanna M Day
  • Helena J Tutill
  • Atul Purohit
  • Michael J Reed
چکیده

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are enzymes that are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form that is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17beta-HSDs have been identified to date, and with one exception, 17beta-HSD type 5 (17beta-HSD5), an aldo-keto reductase, they are all short-chain dehydrogenases/reductases, although overall homology between the enzymes is low. Although named as 17beta-HSDs, reflecting the major redox activity at the 17beta-position of the steroid, the activities of these 15 enzymes vary, with several of the 17beta-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17beta-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review, the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17beta-HSD1, 3 and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Species Used for Drug Testing Reveal Different Inhibition Susceptibility for 17beta-Hydroxysteroid Dehydrogenase Type 1

Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1) for the treatment of breast cancer or endometriosis, novel substances based on 15-substituted estrone were validated. We checked the specificity for different 17beta-HSD types and species. Compounds were tested for specifi...

متن کامل

Can Prostate Specific Antigen Be Used as New Biomarker for Early Diagnosis of Breast Cancer?

Introduction: As a glycoprotein, Plasma Prostate-Specific Antigen (PSA) is mainly produced by prostate epithelial cells and is used as a major diagnostic tool for prostate cancer. A group of researchers relate the elevated number of estrogen receptors in breast cancer samples to the over-production of PSA in this type of cancer. Therefore, the present study aimed to determine the participants' ...

متن کامل

Effect of Aqueous Extract of Physalis Alkek-engi Fruits on the Activity of Ovarian 3beta- and 20alpha-Hydroxysteroid Dehydrogenases in Late Pregnancy in Rat

Background: Aqueous extract of winter cherry (Physalis alkekengi L; family of Solanaceae) fruits (WCF) has long been recommended for fertility control by herbalists in Iran. The effect of this extract on lowering serum progesterone levels has been reported previously. Objective: To study the effects of WCF extract on the activities of ovarian 3β-hydroxysteroid dehydrogenase (3β-HSD) responsible...

متن کامل

Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis.

Estrogen is the most important known factor that stimulates the growth of endometriosis. Estrogen delivery to endometriotic implants was classically viewed to be only via the circulating blood in an endocrine fashion. We recently uncovered an autocrine positive feedback mechanism, which favored the continuous production of estrogen and prostaglandin (PG)E2 in the endometriotic stromal cells. Th...

متن کامل

Estrogen metabolizing enzymes in endometrium and endometriosis.

BACKGROUND Estradiol (E(2)) is an important promoter of the growth of both eutopic and ectopic endometrium. The findings with regard to the expression and activity of steroidogenic enzymes in endometrium of controls, in endometrium of endometriosis patients and in endometriotic lesions are not consistent. METHODS In this study, we have looked at the mRNA expression and protein levels of a ran...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Endocrine-related cancer

دوره 15 3  شماره 

صفحات  -

تاریخ انتشار 2008