New Marine Fungal Deoxy-14,15-Dehydroisoaustamide Resensitizes Prostate Cancer Cells to Enzalutamide

Abstract

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.

Metabolite profiles of Paragliomastix luzulae (formerly named as Acremonium striatisporum) KMM 4401 and its co-cultures with Penicillium hispanicum KMM 4689

“…luzulae KMM 4401 increased, but the production of deoxyisoaustamide alkaloids was less than in case of simultaneous inoculation. Deoxyisoaustamide alkaloids have promising biological activities [ 32 , 33 ] and co-cultivation of P. hispanicum KMM 4689 and Px. luzulae KMM 4401 with simultaneous inoculation can be one of the ways to obtain them in large quantities for future investigations of its bioactivities and semi-synthesis of unique minor derivatives.…”

“…In addition, the strain KMM 4401 was cultivated with the marine fungus Penicillium hispanicum KMM 4689 at two different inoculation times (simultaneously or sequentially after 14 days) to determine whether and how inoculation time affects the production of secondary metabolites. The marine strain P. hispanicum KMM 4689 was found to be a source of structurally interesting desoxyisoaustamide-related alkaloids [ 16 ] with promising bioactivity [ 17 ], and several studies on its fermentation have been carried out [ 18 ].…”

Novel Bioactive Natural Products from Marine-Derived Penicillium Fungi: A Review (2021–2023)

“…Among of them, communesins M-P (192-195) (Figure 5) were isolated and showed moderate cy-totoxicity against KB and MCF-7 human cancer cell lines in comparison to the positive control docetaxel [9]. The coral-derived P. dimorphosporum KMM 4689 yielded the very first deoxyisoaustamide alkaloid deoxy-14,15-dehydroisoaustamide (196) [70] and seven deoxyisoaustamide derivatives (197-203) [71] (Figure 5). Deoxyisoaustamide derivatives 199, 201 and 202 (Figure 5) showed a statistical increase in paraquat-treated Neuro-2a cell viability by 30-39% at a concentration of 1 µM.…”