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

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

  • Sci Rep. 2022 Aug 9;12(1):13570. doi: 10.1038/s41598-022-17447-x.
Sergey A Dyshlovoy  # 1 2 3,  Larisa K Shubina  # 4,  Tatyana N Makarieva 4,  Jessica Hauschild 5 6,  Nadja Strewinsky 5,  Alla G Guzii 4,  Alexander S Menshov 4,  Roman S Popov 4,  Boris B Grebnev 4,  Tobias Busenbender 5,  Su Jung Oh-Hohenhorst 6 7,  Tobias Maurer 6 8,  Derya Tilki 6 8,  Markus Graefen 6,  Carsten Bokemeyer 5,  Valentin A Stonik 4,  Gunhild von Amsberg 5 6
Affiliations

Affiliations

  • 1 Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. s.dyshlovoy@uke.de.
  • 2 Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany. s.dyshlovoy@uke.de.
  • 3 Institute of Science-Intensive Technologies and Advanced Materials, Far Eastern Federal University, Vladivostok, Russian Federation. s.dyshlovoy@uke.de.
  • 4 G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
  • 5 Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 6 Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
  • 7 Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) Et Institut du Cancer de Montréal, Montreal, QC, Canada.
  • 8 Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
  • # Contributed equally.
PMID: 35945234 DOI: 10.1038/s41598-022-17447-x
Abstract

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.

Figures
Products