Cytotoxic N-Methylpretrichodermamide B Reveals Anticancer Activity and Inhibits P-Glycoprotein in Drug-Resistant Prostate Cancer Cells
Sergey A. Dyshlovoy,
Tobias Busenbender,
Jessica Hauschild,
Elena V. Girich,
Malte Kriegs,
Konstantin Hoffer,
Markus Graefen,
Anton N. Yurchenko,
Carsten Bokemeyer,
Gunhild von Amsberg
Affiliations
Sergey A. Dyshlovoy
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
Tobias Busenbender
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
Jessica Hauschild
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
Elena V. Girich
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Prospect 100 let Vladivostoku 159, 690022 Vladivostok, Russia
Malte Kriegs
Department of Radiotherapy & Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
Konstantin Hoffer
Department of Radiotherapy & Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
Markus Graefen
Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
Anton N. Yurchenko
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Prospect 100 let Vladivostoku 159, 690022 Vladivostok, Russia
Carsten Bokemeyer
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
Gunhild von Amsberg
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
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.
