Molecular and Cellular Pharmacology
Combination of ginsenoside Rg3 with docetaxel enhances the susceptibility of prostate cancer cells via inhibition of NF-κB

https://doi.org/10.1016/j.ejphar.2009.12.018Get rights and content

Abstract

Ginsenoside Rg3 has been a subject of interest for use as a cancer preventive or therapeutic agent. Nuclear factor-kappa (NF-κB) is constitutively activated in prostate cancer, and gives cancer cells resistance to chemotherapeutic agents. To investigate whether Rg3 can suppress the activation of NF-κB, and thus increase susceptibility of prostate (LNCaP and PC-3, DU145) cells against chemotherapeutics, prostate cancer cell growth as well as activation of NF-κB was examined. We found that a combination treatment of Rg3 (50 µM) with a conventional agent docetaxel (5 nM) was more effective in the inhibition of prostate cancer cell growth and induction of apoptosis as well as G0/G1 arrest accompanied with the significant inhibition of NF-κB activity than those by treatment of Rg3 or docetaxel alone. It was also found that NF-κB target gene expression of Bax, caspase-3, and caspase-9 was much more significantly enhanced, but the expression of Bcl-2, inhibitor of apoptosis protein (IAP-1) and X chromosome IAP (XIAP), and the expression of cell cycle regulatory proteins cyclin B, D1 and E, and cyclin dependent kinases 2 and 4 was also much more significantly inhibited by the combination treatment. The combination of Rg3 (50 µM) with cisplatin (10 µM) and doxorubicin (2 µM) was also more effective in the inhibition of prostate cancer cell growth and NF-κB activity than those by the treatment of Rg3 or chemotherapeutics alone. These results indicate that ginsenoside Rg3 inhibits NF-κB, and enhances the susceptibility of prostate cancer cells to docetaxel and other chemotherapeutics. Thus, ginsenoside Rg3 could be useful as an anti-cancer agent.

Introduction

Prostate cancer is the most commonly diagnosed cancer in men. Unfortunately, there is no effective treatment for prostate cancer (Jemal et al., 2002). Docetaxel, a semi-synthetic taxoid produced from the needles of the European yew (Taxus baccata) tree, is an antineoplastic drug. As a chemotherapeutic agent, docetaxel is one of the most important new and active chemotherapeutic agents developed in the recent years, and has a potential activity against human solid tumors including prostate cancers that are refractory to conventional anti-cancer agents (Diaz-Rubio, 2004). However, the use of high dose docetaxel always induced toxic reactions, and significant toxicity had precluded the use of docetaxel as a monotherapy for cancer (Cortes and Pazdur, 1995, Fossella et al., 2000, 2004; Tedesco et al., 2004). Since low or moderate doses of docetaxel have no significant antitumor activity in patients (Ferraresi et al., 2000, Okada et al., 1999, Ryan et al., 2002), ways to reduce the dose of docetaxel without affecting its antitumor activity should be examined. In this regard, dietary supplements as well as phytotherapeutic agents with anti-cancer efficacy and least toxicity to normal tissues are suggested as possible candidates to be investigated for their synergistic efficacy in combination with anti-cancer drugs (Agarwal, 2000, Hong and Sporn, 1997, Kelloff, 2000, Sporn and Suh, 2000).

NF-κB mediates chemotherapeutic resistance through the expression of genes participating in malignant conversion and tumor promotion (Garg and Aggarwal, 2002, Greten et al., 2004, Pikarsky et al., 2004a, Pikarsky et al., 2004b). In primary prostate cancer tissue samples, constitutive NF-κB activity has been suggested to have prognostic importance for a subset of primary tumors (Suh and Rabson, 2004). Moreover, NF-κB was shown to be constitutively activated in human androgenin dependent prostate cancer cell lines (Palayoor et al., 1999). In addition, several reports have suggested that chemotherapeutic-induced NF-κB activity mediates survival signals that counteract apoptosis (Dong et al., 2002, Huang et al., 2000, Oyaizu et al., 2001, Uzzo et al., 2002), and it may be critical in the development of drug resistance in cancer cells (Dong et al., 2002). Therefore, several agents that are able to inhibit NF-κB might be considered as an adjuvant approach in combination with chemotherapeutics for lung cancer (Oyaizu et al., 2001), prostate cancer (Uzzo et al., 2002), pancreatic cancer (Zhang et al., 2003), breast cancer (Weldon et al., 2001), and colon cancer (Yance and Sagar, 2006).

Ginseng has been used in Asian countries for the treatment and prevention of various diseases, including cancer (Ryan et al., 2002). People consuming ginseng are at lower risk for stomach, lung, liver, pancreas, ovary, and colon cancers (Ferraresi et al., 2000). A novel ginsenoside, Rg3 from Panax notoginseng has an anti-cancer activity (Mabuchi et al., 2004). It was previously found that Rg3 has an inhibitory effect on the inactivation of NF-κB, thus inhibiting colon cancer cell growth (Anil et al., 2002). In this study, we evaluated Rg3 for its effects against prostate cancer, emphasizing combination therapy, and inhibition of NF-κB as a molecular mechanism.

Section snippets

Materials

Rg3 (structure shown in Fig. 1A), a major ginsenoside derived from heat-processed ginseng (Sun ginseng), was prepared and purified as described previously (Kim et al., 2000). Docetaxel was produced by the procedure of semi-synthesis, and purified. Briefly, crude docetaxel was obtained from semi-synthesis by the reaction of dehydroxybaccatin III with (3R,4S)-1-t-boc-3-triethylsilyloxy-4-phenylazetidin-2-one, and then purified by recrystallization with MeOH/DW(methanol/distilled water) solution.

Effect of the combination of Rg3 and docetaxel on the NF-κB activation

We were interested whether Rg3 inhibits prostate cancer cell growth by inactivation of NF-κB because activation of NF-κB is critical in prostate cancer cell survival and resistance against chemotherapeutics. Constituted activation of NF-κB was observed in prostate, and the treatment of docetaxel slightly changed (either increase or decrease) the NF-κB DNA binding activity by 1 or 5 nM of docetaxel in LNCaP, DU145, PC-3, and then decreased by 10 nM docetaxel as similar to a previous report (Lee et

Discussion

The present study indicates that Rg3 strongly augments the growth inhibitory effect of docetaxel and other therapeutic agents on prostate cancer cell by inactivation of NF-κB. As a chemotherapeutic agent, docetaxel has one of the most potential activities against human solid tumors including prostate cancers (Diaz-Rubio, 2004). However, the use of high dose docetaxel induces significant toxicity (Cortes and Pazdur, 1995, Fossella et al., 2000, 2004; Tedesco et al., 2004), but low or moderate

Acknowledgments

This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean Government (MOST) (R13-2008-001-00000-00), and by the grant of the Korean Ministry of Education Science and Technology (The regional Core Research program/Chungbuk BIT Research-Oriental University Consortium).

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