ABSTRACT
BACKGROUND: Prostate cancer (PCa) ranks as the second most prevalent cancer in men, with advanced stages posing significant treatment challenges. Given its solid tumor nature, PCa is highly susceptible to hypoxia, a condition associated with resistance to radiation and chemotherapy, metastasis, and unfavorable patient outcomes. Hypoxia-inducible factors (HIFs) play a pivotal role in cancer cell adaptation to hypoxic environments, contributing to treatment resistance. Consequently, inhibitors targeting HIFs hold promise for cancer therapy. METHODS: In this study, we aimed to characterize novel HIF-1α inhibitors including Sodwanones A (1), B (2), C (3), G (4) and Yardenone 2 (5) isolated from marine sponges belonging to the Axinella genus. Our investigation evaluated the impact of these compounds on various aspects of HIF-1α regulation, including stabilization, nuclear localization, expression of HIF-1 target genes (while sparing HIF-2 target genes), cellular metabolism, as well as cell proliferation and viability in prostate cells under hypoxic conditions. RESULTS: Our findings revealed that among the compounds tested, Yardenone 2 exhibited notable effects in hypoxia: it destabilized HIF-1α at the protein level, decreased its nuclear localization, selectively altered the expression of HIF-1 target genes, and restrained cell proliferation in aggressive PC3 prostate cancer cells as well as in an MSK-PCa3 patient-derived organoid line. Moreover, it affected the morphology of these organoid. Yardenone 2 was also compared to Docetaxel, a specific microtubule inhibitor and a drug used in the treatment of prostate cancer. The comparison between the two compounds revealed notable differences, such as a lack of specificity to hypoxic cells of Docetaxel. CONCLUSION: These results mark the first demonstration that Yardenone 2 functions as a cytostatic-like inhibitor impacting microtubules, specifically targeting hypoxic cancer cells. This discovery suggests a promising avenue for novel therapeutic interventions in prostate cancer.
Subject(s)
Cell Proliferation , Hypoxia-Inducible Factor 1, alpha Subunit , Prostatic Neoplasms , Humans , Male , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , Cell Proliferation/drug effects , Cell Line, Tumor , Animals , Porifera/chemistry , Gene Expression Regulation, Neoplastic/drug effects , Antineoplastic Agents/pharmacology , Cell Hypoxia/drug effectsABSTRACT
The Verongida order comprises several sponge families, such as Aplysinellidae, Aplysinidae, Ianthellidae, and Pseudoceratinidae, reported for producing bromotyrosine-derived compounds. First identified in 1913, bromotyrosine derivatives have since captivated interest notably for their antitumor and antimicrobial properties. To date, over 360 bromotyrosine derivatives have been reported. Our review focuses specifically on bromotyrosine derivatives newly reported from 2004 to 2023, by summarizing current knowledge about their chemical diversity and their biological activities.