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

被引：12

作者：

Dyshlovoy, Sergey A. ^{[1
,2
,3
]}

Shubina, Larisa K. ^{[4
]}

Makarieva, Tatyana N. ^{[4
]}

Hauschild, Jessica ^{[1
,2
]}

Strewinsky, Nadja ^{[1
]}

Guzii, Alla G. ^{[4
]}

Menshov, Alexander S. ^{[4
]}

Popov, Roman S. ^{[4
]}

Grebnev, Boris B. ^{[4
]}

Busenbender, Tobias ^{[1
]}

Oh-Hohenhorst, Su Jung ^{[2
,5
,6
]}

Maurer, Tobias ^{[2
,7
]}

Tilki, Derya ^{[2
,7
]}

Graefen, Markus ^{[2
]}

Bokemeyer, Carsten ^{[1
]}

Stonik, Valentin A. ^{[4
]}

von Amsberg, Gunhild ^{[1
,2
]}

机构：

[1] Univ Med Ctr Hamburg Eppendorf, Hubertus Wald Tumorzentrum Univ Canc Ctr Hamburg, Dept Oncol Hematol & Bone Marrow Transplantat Sec, Hamburg, Germany

[2] Univ Hosp Hamburg Eppendorf, Prostate Canc Ctr, Martini Klin, Hamburg, Germany

[3] Far Eastern Fed Univ, Inst Sci Intens Technol & Adv Mat, Vladivostok, Russia

[4] Russian Acad Sci, GB Elyakov Pacific Inst Bioorgan Chem, Far East Branch, Vladivostok, Russia

[5] Ctr Rech Ctr Hosp Univ Montreal CRCHUM, Montreal, PQ, Canada

[6] Inst Canc Montreal, Montreal, PQ, Canada

[7] Univ Hosp Hamburg Eppendorf, Dept Urol, Hamburg, Germany

来源：

SCIENTIFIC REPORTS | 2022年 / 12卷 / 01期

关键词：

ANDROGEN RECEPTOR; NATURAL-PRODUCTS; APLYSILLA-ROSEA; CONSTITUENTS; METABOLITES; TAXANE;

D O I：

10.1038/s41598-022-17447-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-15 alpha,17 beta-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.

引用

页数：13

共 41 条

[41] Spongian Diterpenoids Inhibit Androgen Receptor Activity
Yang, Yu Chi
Meimetis, Labros G.
Tien, Amy H.
Mawji, Nasrin R.
Carr, Gavin
Wang, Jun
Andersen, Raymond J.
Sadar, Marianne D.
[J]. MOLECULAR CANCER THERAPEUTICS, 2013, 12 (05) : 621 - 631

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