New diterpenes from the marine sponge Spongionella sp. overcome drug resistance in prostate cancer by inhibition of P-glycoprotein
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New diterpenes from the marine sponge Spongionella sp. overcome drug resistance in prostate cancer by inhibition of P-glycoprotein. / Dyshlovoy, Sergey A; Shubina, Larisa K; Makarieva, Tatyana N; Hauschild, Jessica; Strewinsky, Nadja; Guzii, Alla G; Menshov, Alexander S; Popov, Roman S; Grebnev, Boris B; Busenbender, Tobias; Oh-Hohenhorst, Su Jung; Maurer, Tobias; Tilki, Derya; Graefen, Markus; Bokemeyer, Carsten; Stonik, Valentin A; von Amsberg, Gunhild.
In: SCI REP-UK, Vol. 12, No. 1, 13570, 09.08.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - New diterpenes from the marine sponge Spongionella sp. overcome drug resistance in prostate cancer by inhibition of P-glycoprotein
AU - Dyshlovoy, Sergey A
AU - Shubina, Larisa K
AU - Makarieva, Tatyana N
AU - Hauschild, Jessica
AU - Strewinsky, Nadja
AU - Guzii, Alla G
AU - Menshov, Alexander S
AU - Popov, Roman S
AU - Grebnev, Boris B
AU - Busenbender, Tobias
AU - Oh-Hohenhorst, Su Jung
AU - Maurer, Tobias
AU - Tilki, Derya
AU - Graefen, Markus
AU - Bokemeyer, Carsten
AU - Stonik, Valentin A
AU - von Amsberg, Gunhild
N1 - © 2022. The Author(s).
PY - 2022/8/9
Y1 - 2022/8/9
N2 - Spongian diterpenes are a group of marine natural compounds possessing various biological activities. However, their anticancer activity is still poorly studied and understood. We isolated six spongian diterpenes from the marine sponge Spongionella sp., including one new spongionellol A and five previously known molecules. The structures were elucidated using a detailed analysis MS and NMR spectra as well as by comparison with previously reported data. Two of them, namely, spongionellol A and 15,16-dideoxy-15α,17β-dihydroxy-15,17-oxidospongian-16-carboxylate-15,17-diacetate exhibited high activity and selectivity in human prostate cancer cells, including cells resistant to hormonal therapy and docetaxel. The mechanism of action has been identified as caspase-dependent apoptosis. Remarkably, both compounds were able to suppress expression of androgen receptor (AR) and AR-splice variant 7, as well as AR-dependent signaling. The isolated diterpenes effectively inhibited drug efflux mediated by multidrug-resistance protein 1 (MDR1; p-glycoprotein). Of note, a synergistic effect of the compounds with docetaxel, a substrate of p-glycoprotein, suggests resensitization of p-glycoprotein overexpressing cells to standard chemotherapy. In conclusion, the isolated spongian diterpenes possess high activity and selectivity towards prostate cancer cells combined with the ability to inhibit one of the main drug-resistance mechanism. This makes them promising candidates for combinational anticancer therapy.
AB - Spongian diterpenes are a group of marine natural compounds possessing various biological activities. However, their anticancer activity is still poorly studied and understood. We isolated six spongian diterpenes from the marine sponge Spongionella sp., including one new spongionellol A and five previously known molecules. The structures were elucidated using a detailed analysis MS and NMR spectra as well as by comparison with previously reported data. Two of them, namely, spongionellol A and 15,16-dideoxy-15α,17β-dihydroxy-15,17-oxidospongian-16-carboxylate-15,17-diacetate exhibited high activity and selectivity in human prostate cancer cells, including cells resistant to hormonal therapy and docetaxel. The mechanism of action has been identified as caspase-dependent apoptosis. Remarkably, both compounds were able to suppress expression of androgen receptor (AR) and AR-splice variant 7, as well as AR-dependent signaling. The isolated diterpenes effectively inhibited drug efflux mediated by multidrug-resistance protein 1 (MDR1; p-glycoprotein). Of note, a synergistic effect of the compounds with docetaxel, a substrate of p-glycoprotein, suggests resensitization of p-glycoprotein overexpressing cells to standard chemotherapy. In conclusion, the isolated spongian diterpenes possess high activity and selectivity towards prostate cancer cells combined with the ability to inhibit one of the main drug-resistance mechanism. This makes them promising candidates for combinational anticancer therapy.
KW - ATP Binding Cassette Transporter, Subfamily B/metabolism
KW - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
KW - Animals
KW - Diterpenes/chemistry
KW - Docetaxel/pharmacology
KW - Drug Resistance
KW - Humans
KW - Male
KW - Molecular Structure
KW - Porifera/metabolism
KW - Prostatic Neoplasms/drug therapy
U2 - 10.1038/s41598-022-17447-x
DO - 10.1038/s41598-022-17447-x
M3 - SCORING: Journal article
C2 - 35945234
VL - 12
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
IS - 1
M1 - 13570
ER -