A new steroidal 5,7-diene derivative, 3beta-hydroxyandrosta-5,7-diene-17beta-carboxylic acid, shows potent anti-proliferative activity.

Abstract

The new steroidal 5,7-diene, 3beta-hydroxyandrosta-5,7-diene-17beta-carboxylic acid (17-COOH-7DA), was synthesized from 21-acetoxypregnenolone, with the oxidative cleavage of the side chain being dependent on the presence of oxygen. In human epidermal (HaCaT) keratinocytes, 17-COOH-7DA inhibited proliferation in a dose-dependent manner, starting at a dose as low as 10(-11) M. This inhibition was accompanied by decreased expression of epidermal growth factor receptor, bcl2 and cyclin E2 mRNAs and by increased expression of involucrin mRNA. Inhibition of proliferation was associated with slowing of the cell cycle in G1/G0 phases but not with cell death. 17-COOH-7DA was significantly more potent than pregnenolone, 17-COOH-pregnenolone, 17-COOCH(3)-7DA and calcitriol. 17-COOH-7DA also inhibited proliferation of normal human epidermal melanocytes and human and hamster melanoma lines, however, with lower potency than for keratinocytes. In normal human dermal fibroblasts 17-COOH-7DA stimulated proliferation in serum-free media but inhibited it in the presence of 5% serum. 17-COOH-7DA inhibited cell colony formation of human and hamster melanoma cells, and induced monocyte-like differentiation of human HL60 leukemia cells. Thus, the new steroidal 5,7-diene, 17-COOH-7DA, can serve as an inhibitor of proliferation of normal keratinocytes and normal and malignant melanocytes, as a condition-dependent regulator of fibroblast proliferation and a stimulator of leukemia cell differentiation.

• Authors: Tae-Kang Kim, Jianjun Chen, Wei Li, Jordan Zjawiony, Duane Miller, Zorica Janjetovic, Robert C Tuckey, Andrzej Slominski
• Journal: Steroids (Steroids) Vol. 75 Issue 3 Pg. 230-9 (Mar 2010) ISSN: 1878-5867 [Electronic] United States
• PMID: 20025893 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright 2009 Elsevier Inc. All rights reserved.

Chemical References

• 3-hydroxyandrosta-5,7-diene-17-carboxylic acid
• Androstadienes
• Antineoplastic Agents
• CCNE1 protein, human
• Carboxylic Acids
• Cyclin E
• Oncogene Proteins
• Protein Precursors
• Proto-Oncogene Proteins c-bcl-2
• Steroids
• involucrin
• ErbB Receptors

Topics

• Androstadienes (chemical synthesis, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Carboxylic Acids (chemical synthesis, chemistry, pharmacology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cricetinae
• Cricetulus
• Cyclin E (genetics, metabolism)
• ErbB Receptors (genetics, metabolism)
• HL-60 Cells
• Humans
• Keratinocytes (cytology, drug effects, metabolism)
• Melanocytes (cytology, drug effects, metabolism)
• Molecular Structure
• Nuclear Magnetic Resonance, Biomolecular
• Oncogene Proteins (genetics, metabolism)
• Protein Precursors (genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Steroids (chemical synthesis, chemistry, pharmacology)