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

TY - JOUR

T1 - Cytotoxic N-Methylpretrichodermamide B Reveals Anticancer Activity and Inhibits P-Glycoprotein in Drug-Resistant Prostate Cancer Cells

AU - Dyshlovoy, Sergey A.

AU - Busenbender, Tobias

AU - Hauschild, Jessica

AU - Girich, Elena V.

AU - Kriegs, Malte

AU - Hoffer, Konstantin

AU - Graefen, Markus

AU - Yurchenko, Anton N.

AU - Bokemeyer, Carsten

AU - Amsberg, Gunhild von

PY - 2022/9/23

Y1 - 2022/9/23

N2 - 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.

AB - 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.

KW - Humans

KW - Male

KW - Antineoplastic Agents/pharmacology

KW - Apoptosis

KW - ATP Binding Cassette Transporter, Subfamily B

KW - ATP Binding Cassette Transporter, Subfamily B, Member 1/pharmacology

KW - Caspase 3/metabolism

KW - Cell Line, Tumor

KW - Docetaxel/pharmacology

KW - Hormones/pharmacology

KW - Phosphatidylserines/pharmacology

KW - Prostatic Neoplasms/drug therapy

KW - Drug Resistance, Neoplasm

U2 - 10.3390/md20100597

DO - 10.3390/md20100597

M3 - SCORING: Journal article

C2 - 36286421

VL - 20

JO - MAR DRUGS

JF - MAR DRUGS

SN - 1660-3397

IS - 10

M1 - 597

ER -