New diterpenes from the marine sponge Spongionella sp. overcome drug resistance in prostate cancer by inhibition of P-glycoprotein

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 -