Lipoamino Acid-Modified GnRH Analogs with Receptor-Mediated Antiproliferative Activity in Prostate and Ovarian Cancer Cells

Gonadotropin-releasing hormone (GnRH) analogs (e.g., triptorelin) are developed to treat hormone-dependent reproductive cancers. However, these analogs lack any significant direct antitumor activity to make them suitable for hormone-refractory reproductive cancers. In this study, we modified GnRH peptide and triptorelin to improve their stability, pharmacokinetic properties, and potency and subsequently broaden their clinical applications in cancer. We investigated biological properties of lipid-modified GnRH analogs, with/without D-amino acid substitution at position 6 to yield GnRH- and triptorelin-based derivatives, respectively, in prostate and ovarian cancer cells. We showed that the improved stability due to lipid-modification and D-amino acid substitution played a pivotal role in enhancing GnRH receptor-mediated direct antiproliferative activity (up to 4.5-fold higher than triptorelin) and gonadotropin-releasing potency. Furthermore, sex steroids played significant but contrasting roles in regulating the direct antiproliferative activity of the lipopeptides in cancer cells. The superior activity of these GnRH analogs over triptorelin renders promises for developing new GnRH receptor ligands to treat hormone-dependent and -refractory cancers, as well as emerging new targeting moieties for the delivery of anticancer agents in GnRH receptor-overexpressing cancers.

BRENNER TUMOR -AN OVERVIEW

The ovaries are an essential part of the reproductive system to produce ovum which helps to regulate hormones and play a prime role in pregnancy and fertility in women health. In contrast, Excess growth of abnormal tissue in any part of ovaries affect the normal reproductive function among women. Generally, Ovarian tumors are prevalent forms of neoplasm among women and it attributes for about 30% of female reproductive cancers. Ovarian cancer is the one of the most habitual female carcinomas, and the fourth main cause of death among cancer demise in female. These tumors act in different ways, and predominantly they are discovered after procuring a bigger volume. There are four major groups of ovarian cancer which are surface epithelial, sex cord or stromal, germ cell and metastatic tumors. Brenner tumor is one of the subtypes of surface epithelial carcinoma which resembles transitional neoplasm of urinary tract.

Targeting Aquaporins in Novel Therapies for Male and Female Breast and Reproductive Cancers

Aquaporins are membrane channels in the broad family of major intrinsic proteins (MIPs), with 13 classes showing tissue-specific distributions in humans. As key physiological modulators of water and solute homeostasis, mutations, and dysfunctions involving aquaporins have been associated with pathologies in all major organs. Increases in aquaporin expression are associated with greater severity of many cancers, particularly in augmenting motility and invasiveness for example in colon cancers and glioblastoma. However, potential roles of altered aquaporin (AQP) function in reproductive cancers have been understudied to date. Published work reviewed here shows distinct classes aquaporin have differential roles in mediating cancer metastasis, angiogenesis, and resistance to apoptosis. Known mechanisms of action of AQPs in other tissues are proving relevant to understanding reproductive cancers. Emerging patterns show AQPs 1, 3, and 5 in particular are highly expressed in breast, endometrial, and ovarian cancers, consistent with their gene regulation by estrogen response elements, and AQPs 3 and 9 in particular are linked with prostate cancer. Continuing work is defining avenues for pharmacological targeting of aquaporins as potential therapies to reduce female and male reproductive cancer cell growth and invasiveness.