Influence of GRPR and BDNF/TrkB signaling on the viability of breast and gynecologic cancer cells.

Neuropeptide and neurotrophin receptors are increasingly important molecular targets in cancer. Scientific findings indicate that compounds blocking gastrin-releasing peptide receptors (GRPR) or tropomyosin receptor kinase (Trk) receptors are likely to have antiproliferative activities against cancer cells. The present study aimed to demonstrate that, in contrast to previous findings, GRPR activation reduces, whereas its blockade increases the viability of breast, ovarian and cervical cancer cell lines. However, consistent with previous studies, Trk inhibition was demonstrated to reduce the viability of these cells. MCF-7 (breast), OVCAR-3 (ovarian) and HeLa (cervical) human cancer cell lines were treated with GRP, the GRPR antagonists RC-3095 and RC-3940-II, brain-derived neurotrophic factor (BDNF) and the Trk antagonist K252α. Cell viability was measured by the MTT assay. Expression of GRPR and BDNF was confirmed with reverse transcription-polymerase chain reaction (RT-PCR). GRP reduced, whereas RC-3940-II enhanced the viability of the three cell lines. Treatment with K252α inhibited the viability of the cell lines, while BDNF increased the viability of OVCAR-3 cells. The results supported the hypothesis that GRPR and BDNF/TrkB signaling regulates cancer cell viability. Most importantly, these findings are the first to demonstrate that GRPR blockade can stimulate, rather than inhibits the viability of breast and gynecologic cancer cell lines.

Emerging therapeutic agents for cervical cancer.

Cervical cancer is the second most frequent malignancy affecting women worldwide. The highest incidences occur in the developing world, where, in most countries, cervical cancer is the leading cause of cancer mortality in women. Although surgery and chemoradiotherapy can cure 80-95% of women with early stage cancer and 60% of locoregionally advanced cancer, the recurrent and metastatic disease remains a major cause of cancer death. The current cytotoxic treatment options for advanced and metastatic cancer demonstrate modest results, with response rates of maximum 30% and overall survival of less than 10 months. Given this limited degree of success with conventional therapies, interest has increased in other therapeutic alternatives. In this way, targeted agents are emerging as potential candidates for improving survival in cervical cancer patients. In this review we highlight the main current therapeutic strategies for cervical cancer and summarize the most relevant patents from the latest five years. Special attention was given to patents with potential applications in the clinical practice.

Targeting the bombesin/gastrin-releasing peptide receptor to treat sepsis.

Sepsis is a complex, multifactorial syndrome that can develop into conditions of different severity, described as septic shock or severe sepsis. In spite of the great progress in understanding the mechanisms involved in the pathogenesis and management of sepsis, only a few therapeutic strategies were able to show a decrease in the mortality from septic shock. Although sepsis consists on a systemic inflammatory response, the anti-inflammatory therapies have failed to improve the outcome of critically ill patients. Here the role of gastrin-releasing peptide in immune processes is reviewed and the data that have prompted the recent patent for GRP receptor antagonists RC-3095 as a therapeutic agent on inflammatory conditions are described.