New Marine Fungal Deoxy-14,15-Dehydroisoaustamide Resensitizes Prostate Cancer Cells to Enzalutamide.
Sergey A DyshlovoyOlesya I ZhuravlevaJessica HauschildTobias BusenbenderDmitry N PelageevAnton Nikolaevich YurchenkoYuliya V KhudyakovaAlexandr S AntonovMarkus GraefenCarsten BokemeyerGunhild von AmsbergPublished in: Marine drugs (2023)
Marine fungi serve as a valuable source for new bioactive molecules bearing various biological activities. In this study, we report on the isolation of a new indole diketopiperazine alkaloid deoxy-14,15-dehydroisoaustamide ( 1 ) from the marine-derived fungus Penicillium dimorphosporum KMM 4689 associated with a soft coral. The structure of this metabolite, including its absolute configuration, was determined by HR-MS, 1D and 2D NMR as well as CD data. Compound 1 is a very first deoxyisoaustamide alkaloid possessing two double bonds in the proline ring. The isolated compound was noncytotoxic to a panel of human normal and cancer cell lines up to 100 µM. At the same time, compound 1 resensitized prostate cancer 22Rv1 cells to androgen receptor (AR) blocker enzalutamide. The mechanism of this phenomenon was identified as specific drug-induced degradation of androgen receptor transcription variant V7 (AR-V7), which also resulted in general suppression of AR signaling. Our data suggest that the isolated alkaloid is a promising candidate for combinational therapy of castration resistant prostate cancer, including drug-resistant subtypes.
Keyphrases
- prostate cancer
- drug resistant
- drug induced
- liver injury
- multidrug resistant
- radical prostatectomy
- acinetobacter baumannii
- electronic health record
- induced apoptosis
- big data
- mycobacterium tuberculosis
- endothelial cells
- papillary thyroid
- mass spectrometry
- cell cycle arrest
- multiple sclerosis
- ms ms
- high resolution
- magnetic resonance
- transcription factor
- adverse drug
- squamous cell carcinoma
- data analysis
- cystic fibrosis
- young adults
- endoplasmic reticulum stress
- replacement therapy