The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer

TY - JOUR

T1 - The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer

AU - Dyshlovoy, Sergey A

AU - Menchinskaya, Ekaterina S

AU - Venz, Simone

AU - Rast, Stefanie

AU - Amann, Kerstin

AU - Hauschild, Jessica

AU - Otte, Katharina

AU - Kalinin, Vladimir I

AU - Silchenko, Alexandra S

AU - Avilov, Sergey A

AU - Alsdorf, Winfried

AU - Madanchi, Ramin

AU - Bokemeyer, Carsten

AU - Schumacher, Udo

AU - Walther, Reinhard

AU - Aminin, Dmitry L

AU - Fedorov, Sergey N

AU - Shubina, Larisa K

AU - Stonik, Valentin A

AU - Balabanov, Stefan

AU - Honecker, Friedemann

AU - von Amsberg, Gunhild

N1 - © 2015 UICC.

PY - 2016/3/15

Y1 - 2016/3/15

N2 - Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (CRPC), outcome of patients remains poor due to the development of drug resistance. Thus, new drugs are urgently needed. We investigated efficacy, toxicity and mechanism of action of marine triterpene glycoside frondoside A (FrA) using CRPC cell lines in vitro and in vivo. FrA revealed high efficacy in human prostate cancer cells, while non-malignant cells were less sensitive. Remarkably, proliferation and colony formation of cells resistant to enzalutamide and abiraterone (due to the androgen receptor splice variant AR-V7) were also significantly inhibited by FrA. The marine compound caused cell type specific cell cycle arrest and induction of caspase-dependent or -independent apoptosis. Up-regulation or induction of several pro-apoptotic proteins (Bax, Bad, PTEN), cleavage of PARP and caspase-3 and down-regulation of anti-apoptotic proteins (survivin and Bcl-2) were detected in treated cells. Global proteome analysis revealed regulation of proteins involved in formation of metastases, tumor cell invasion, and apoptosis, like keratin 81, CrkII, IL-1β and cathepsin B. Inhibition of pro-survival autophagy was observed following FrA exposure. In vivo, FrA inhibited tumor growth of PC-3 and DU145 cells with a notable reduction of lung metastasis, as well as circulating tumor cells in the peripheral blood. Increased lymphocyte counts of treated animals might indicate an immune modulating effect of FrA. In conclusion, our results suggest that FrA is a promising new drug for the treatment of mCRPC. Induction of apoptosis, inhibition of pro-survival autophagy, and immune modulatory effects are suspected modes of actions. This article is protected by copyright. All rights reserved.

AB - Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (CRPC), outcome of patients remains poor due to the development of drug resistance. Thus, new drugs are urgently needed. We investigated efficacy, toxicity and mechanism of action of marine triterpene glycoside frondoside A (FrA) using CRPC cell lines in vitro and in vivo. FrA revealed high efficacy in human prostate cancer cells, while non-malignant cells were less sensitive. Remarkably, proliferation and colony formation of cells resistant to enzalutamide and abiraterone (due to the androgen receptor splice variant AR-V7) were also significantly inhibited by FrA. The marine compound caused cell type specific cell cycle arrest and induction of caspase-dependent or -independent apoptosis. Up-regulation or induction of several pro-apoptotic proteins (Bax, Bad, PTEN), cleavage of PARP and caspase-3 and down-regulation of anti-apoptotic proteins (survivin and Bcl-2) were detected in treated cells. Global proteome analysis revealed regulation of proteins involved in formation of metastases, tumor cell invasion, and apoptosis, like keratin 81, CrkII, IL-1β and cathepsin B. Inhibition of pro-survival autophagy was observed following FrA exposure. In vivo, FrA inhibited tumor growth of PC-3 and DU145 cells with a notable reduction of lung metastasis, as well as circulating tumor cells in the peripheral blood. Increased lymphocyte counts of treated animals might indicate an immune modulating effect of FrA. In conclusion, our results suggest that FrA is a promising new drug for the treatment of mCRPC. Induction of apoptosis, inhibition of pro-survival autophagy, and immune modulatory effects are suspected modes of actions. This article is protected by copyright. All rights reserved.

U2 - 10.1002/ijc.29977

DO - 10.1002/ijc.29977

M3 - SCORING: Journal article

C2 - 26695519

VL - 138

SP - 2450

EP - 2465

JO - INT J CANCER

JF - INT J CANCER

SN - 0020-7136

IS - 10

ER -