Cytotoxic N-Methylpretrichodermamide B Reveals Anticancer Activity and Inhibits P-Glycoprotein in Drug-Resistant Prostate Cancer Cells
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Cytotoxic N-Methylpretrichodermamide B Reveals Anticancer Activity and Inhibits P-Glycoprotein in Drug-Resistant Prostate Cancer Cells. / Dyshlovoy, Sergey A.; Busenbender, Tobias; Hauschild, Jessica; Girich, Elena V.; Kriegs, Malte; Hoffer, Konstantin; Graefen, Markus; Yurchenko, Anton N.; Bokemeyer, Carsten; Amsberg, Gunhild von.
In: MAR DRUGS, Vol. 20, No. 10, 597, 23.09.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -