Journal Article Epublish
PubMed: 40427140 DOI: 10.3390/cancers17101643
Growth Hormone-Releasing Hormone (GHRH) Antagonist Peptides Combined with PI3K Isoform Inhibitors Enhance Cell Death in Prostate Cancer.
Cancers (Basel) 17(10)
Authors: Carlos Perez-Stable, Alicia de Las Pozas, Medhi Wangpaichitr, Wei Sha, Haibo Wang, Renzhi Cai, Andrew V Schally
Affiliations
- Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA.
- Geriatric Research, Education, and Clinical Center, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA.
- Division of Gerontology & Palliative Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Surgery, Division of Cardiothoracic Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- South Florida VA Foundation for Research and Education, Miami, FL 33125, USA.
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA. Geriatric Research, Education, and Clinical Center, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA. South Florida VA Foundation for Research and Education, Miami, FL 33125, USA. Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Abstract
BACKGROUND
Antagonists of GHRH have experimental therapeutic value, but as single agents are not likely to improve clinical outcomes, especially in advanced prostate cancer resistant to androgen deprivation therapy. Our objective is to identify anti-cancer drugs that, in combination with MIA-602 or -690 GHRH antagonists, increase cell death in all types of prostate cancer.
METHODS/RESULTS
We identified inhibitors of PI3Kα or PI3Kβ that consistently increased cell death when combined with MIA-602/690. The PI3K family is critical in mediating upstream signals from receptors to downstream AKT/mTOR signaling pathways and has an important role in cancer progression. The results revealed that MIA-602/690 alone decreased androgen receptors and likely enhanced PI3K (negative feedback), which was then countered by the addition of PI3K inhibitors. Furthermore, the MIA-602/690 + PI3K inhibitor combination affected multiple signaling pathways, including apoptosis (anti-apoptotic Mcl-1L switching to pro-apoptotic Mcl-1S), proliferation (E2F1, cyclin A), PI3Kα/β, AKT, and ERK. Similar results were obtained with a more clinically relevant acetate salt form of MIA-602/690. The identification of PI3K as a drug target for prostate cancer is significant because PTEN (negative regulator of PI3K) loss of function occurs in 40-50% and PIK3CA mutation/amplification occurs in 60% of prostate cancer patients, leading to a poor prognosis.
CONCLUSION
The ability of the MIA-602/690 + PI3K inhibitor combination to alter multiple signaling pathways may weaken the activation of adaptive mechanisms resulting from each drug and improve efficacy.
MeSH
Cells, Growth Hormone-Releasing Hormone, Growth, Pharmaceutical Preparations, Protein Isoforms, Androgens, Receptors, Androgen, Neoplasms, Prostate, Hormones, Prostatic Neoplasms, Therapeutics, Growth Hormone, Cell Death