Potentiation of 2-methoxyestradiol-induced cytotoxicity by blocking endothelin A receptor in prostate cancer cells.
ABSTRACT 2-Methoxyestradiol (2ME2) is an antitumoral and antiangiogenic compound that inhibits hypoxia-inducible factor (HIF)-1, a key regulator of the hypoxic response that promotes tumor progression. HIF-1alpha, the regulated subunit of HIF-1, is overexpressed in premalignant, cancerous and metastatic lesions of prostate. Endothelin (ET)-1 is a HIF target gene and one that plays an important role during prostate bone metastasis via its interaction with endothelin A (ET(A)) receptor. We reasoned that 2ME2 combined with an ET(A) receptor antagonist would induce potent cytotoxic effects in prostate cancer cells.
PC-3 and LNCaP cells were grown alone or cocultured with human osteoblasts. The cells were treated with 2ME2, with an ET(A) receptor antagonist (BQ-123) or with combinations of both compounds. The cells were then evaluated for cytotoxicity, HIF-1alpha protein expression and HIF-1 transcriptional activity.
The combination of 2ME2 with BQ-123 induced synergistic cytotoxic effects in prostate cancer cells and in their cocultures with osteoblasts. No synergism was observed when 2ME2 was combined with the ET(B) selective antagonist, BQ-788. These results correlated with inhibition of HIF-1alpha protein expression, HIF-1 transcriptional activity, and PSA mRNA expression.
The ET(A) receptor antagonist was capable of potentiating the cytotoxic effects of 2ME2 in prostate cancer cells. These effects were apparently mediated through the inhibition of the HIF-1 pathway. Our in vitro data strengthen the rationale for using 2ME2 in combination with ET(A) receptor antagonists for the treatment of metastatic prostate cancer.
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ABSTRACT: Cancer cells, as with most mammalian cells, depend on a continuous supply of glucose; not only as a precursor of glycoproteins, triglycerides and glycogen, but also as an important source of energy. This review concentrates on GLUT transporter expression in both normal and cancerous classical sex-steroid hormone tissues (i.e. breast, uterus, ovary, testis and prostate, among others). Given the importance of estrogen, progesterone and androgens in carcinogenesis, as well as in survival and propagation of these cancers, this review also highlights the current literature on hormone regulation of glucose transporters and on the role of hypoxia in their expression. Given the recent explosion of information on the newer GLUT6-12 family members, a brief overview on their function and general expression has been included. Finally, an insight into the use of glucose transporters as markers of cancer progression and clinical outcome is also discussed.Current Vascular Pharmacology 11/2009; 7(4):534-48. · 2.91 Impact Factor
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ABSTRACT: Oxygen availability is a critical signal for the proper development of many tissues. The transcription factor hypoxia-inducible factor (HIF) plays an important role in maintenance of oxygen homeostasis in all metazoans. Numerous growth and transcription factors have been implicated in the development of the skeletal system. Many of the factors that are up-regulated during hypoxia are downstream of HIF activation. Recent work has demonstrated that HIF has a critical function in cartilage and bone development. We summarize current understanding of the role of HIF in bone and cartilage development.Cytotherapy 04/2009; 11(3):261-7. · 3.06 Impact Factor
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ABSTRACT: ContextNew, effective therapies for castration-resistant prostate cancer (CRPC) are needed to treat this lethal form of the disease. Through an understanding of the biology of endothelin-1 (ET-1) and the endothelin receptors (the endothelin axis) in prostate cancer (PCa), this axis has emerged as a promising target for therapeutic intervention.European Urology Supplements - EUR UROL SUPPL. 01/2009; 8(1):20-28.