Antiestrogenic Therapies in Solid Cancers and Multiple Myeloma

Brigitte      Sola; Jack-Michel      Renoir

doi:10.2174/156652406777435408

Abstract

Estrogens are essential for human health. Their physiological effects are primarily mediated by two types of intracellular estrogen receptors (ERα and ERβ) that function as DNA-binding transcription factors. However, estrogens are also involved in the development and progression of breast cancers. Endocrine therapy aims to reduce the availability of the hormone or to counteract its action. This can be achieved by preventing estrogen production or administrating antiestrogens (AEs), synthetic drugs belonging to several distinct structural categories. Selective estrogen receptor modulators (or SERMs) bind ERs but have a mixed agonist/antagonist profile. Selective estrogen receptor downregulators (or SERDs) are pure antiestrogens, acting by decreasing the level of ERs through their ubiquitinylation and subsequent targeting to the proteasome. We review most of the usual antiestrogenic therapies for estrogen-dependent and estrogen-independent solid cancers and present our recent results on the use of AEs against multiple myeloma. In breast cancer treatments, the most commonly used antiestrogen, tamoxifen, has major limitations: side effects due to its partial agonist activity and constitutive or acquired resistance. We propose that novel AE drug delivery systems may enhance the overall beneficial effects by targeting tumoral cells.

Keywords: benzopyran, Estrogens, Estrogen Receptors, Breast Cancer, Lung Cancer, ANTIESTROGENS