Potentiation of 2-methoxyestradiol-induced cytotoxicity by blocking endothelin A receptor in prostate cancer cells.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Mabjeesh
Nicola J
NJ
Prostate Cancer Research Laboratory, Department of Urology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. nicolam@tasmc.health.gov.il
Shefler
Alexander
A
Amir
Sharon
S
Matzkin
Haim
H
D000077584:2-Methoxyestradiol; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism
D000970:Antineoplastic Agents; D065128:Endothelin Receptor Antagonists; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D004958:Estradiol; D000077584:2-Methoxyestradiol; D017430:Prostate-Specific Antigen; C072247:cyclo(Trp-Asp-Pro-Val-Leu)