2. Academic Validation
  3. Cytotoxic N-Methylpretrichodermamide B Reveals Anticancer Activity and Inhibits P-Glycoprotein in Drug-Resistant Prostate Cancer Cells

Cytotoxic N-Methylpretrichodermamide B Reveals Anticancer Activity and Inhibits P-Glycoprotein in Drug-Resistant Prostate Cancer Cells

  • Mar Drugs. 2022 Sep 23;20(10):597. doi: 10.3390/md20100597.
Sergey A Dyshlovoy 1 2 3,  Tobias Busenbender 1,  Jessica Hauschild 1 2,  Elena V Girich 4,  Malte Kriegs 5 6,  Konstantin Hoffer 5 6,  Markus Graefen 2,  Anton N Yurchenko 4,  Carsten Bokemeyer 1,  Gunhild von Amsberg 1 2
Affiliations

Affiliations

  • 1 Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
  • 2 Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
  • 3 Institute of High Technologies and Advanced Materials, Far Eastern Federal University, FEFU Campus, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia.
  • 4 G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Prospect 100 let Vladivostoku 159, 690022 Vladivostok, Russia.
  • 5 Department of Radiotherapy & Radiation Oncology, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
  • 6 UCCH Kinomics Core Facility, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20461 Hamburg, Germany.
PMID: 36286421 DOI: 10.3390/md20100597
Abstract

N-methylpretrichodermamide B (NB) is a biologically active epidithiodiketopiperazine isolated from several strains of the algae-derived fungus Penicillium sp. Recently, we reported the first data on its activity in human Cancer cells lines in vitro. Here, we investigated the activity, selectivity, and mechanism of action of NB in human prostate Cancer cell lines, including drug-resistant subtypes. NB did not reveal cross-resistance to docetaxel in the PC3-DR cell line model and was highly active in hormone-independent 22Rv1 cells. NB-induced cell death was stipulated by externalization of phosphatidylserine and activation of Caspase-3. Moreover, inhibition of Caspase activity by z-VAD(OMe)-fmk did not affect NB cytotoxicity, suggesting a caspase-independent cell death induced by NB. The compound has a moderate P-glycoprotein (p-gp) substrate-like affinity and can simultaneously inhibit p-gp at nanomolar concentrations. Therefore, NB resensitized p-gp-overexpressing PC3-DR cells to docetaxel. A kinome profiling of the NB-treated cells revealed, among Other things, an induction of mitogen-activated protein kinases JNK1/2 and p38. Further functional analysis confirmed an activation of both kinases and indicated a prosurvival role of this biological event in the cellular response to the treatment. Overall, NB holds promising Anticancer potential and further structure-activity relationship studies and structural optimization are needed in order to improve its biological properties.

Keywords

MAP kinases; N-methylpretrichodermamide B; cytotoxic activity; drug-resistance; marine fungi; p-glycoprotein; prostate cancer.

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