Curcumin induces cell apoptosis in human chondrosarcoma through extrinsic death receptor pathway

doi:10.1016/j.intimp.2012.04.002

International Immunopharmacology

Volume 13, Issue 2, June 2012, Pages 163-169

https://doi.org/10.1016/j.intimp.2012.04.002 Get rights and content

Abstract

Chondrosarcoma is a soft tissue sarcoma with a poor prognosis that is unresponsive to conventional chemotherapy. Surgical treatment leads to severe disability with high rates of local recurrence and life threat. Curcumin, an active compound in turmeric and curry, has been proven to induce tumor apoptosis and inhibit tumor proliferation, invasion, angiogenesis, and metastasis of cancer cells. In this study, we investigated the anticancer effects of curcumin in human chondrosarcoma cells. Curcumin induced apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353) but not in primary chondrocytes. Curcumin induced upregulation of Fas, FasL, and DR5 expression in chondrosarcoma cells. Transfection of cells with Fas, FasL, or DR5 siRNA reduced curcumin-induced cell death. In addition, p53 involved in curcumin-mediated Fas, FasL, and DR5 expression and cell apoptosis in chondrosarcoma cells. Most importantly, animal studies revealed a dramatic 60% reduction in tumor volume after 21 days of treatment. Thus, curcumin may be a novel anticancer agent for the treatment of chondrosarcoma.

Highlights

► Curcumin induces cell apoptosis in chondrosarcoma. ► Extrinsic death receptor pathway is mediated curcumin effects. ► Curcumin increases p53 expression. ► Curcumin inhibits tumor growth in vivo.

Introduction

Chondrosarcomas are malignant tumors showing cartilage differentiation, and it is the third most common primary bone malignancy after myeloma and osteosarcoma. Due to its resistance to both ionizing radiation and chemotherapy, chondrosarcoma is making the management of chondrosarcoma a complicated challenge [1]. Clinically, surgical resection remains the primary mode of therapy for chondrosarcoma. In the absence of an effective adjuvant therapy, this mesenchymal malignancy has a poor prognosis and novel and adequate therapies are needed [2].

Apoptosis is an intracellular suicide program possessing morphologic characteristics and biochemical features, including chromatin condensation, nuclear DNA fragmentation, cell shrinkage, membrane blebbing, and the formation of apoptotic bodies [3], [4]. Apoptosis is a physiological mechanism for eliminating malignant cells or cancer cells without eliciting damage to normal cells or surrounding tissues. Thus, induction of apoptosis in target cells is a key mechanism by which anti-cancer therapy works. To date, two major apoptotic pathways have been described as follows: the extrinsic death receptor-mediated pathway and the intrinsic mitochondrion-initiated pathway. The extrinsic apoptotic pathway originates at membrane death receptors (DRs) such as Fas, DR4, and DR5 and then engages the intracellular apoptotic machinery involving adaptor molecules and proximal caspase-8 as well as distal executioner caspases [5].

p53 is a proapoptotic gene [6]. It has been reported that p53 triggers apoptosis through both DR and mitochondrial apoptotic pathways [7]. DRs such as DR4, DR5, and Fas are increased by p53-dependent transcriptional activation [8]. Interaction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor family of proteins, with DR4 and DR5 leads to recruitment of the adaptor protein FADD and initiator caspase-8 to the death-inducing signaling complex [9]. This results in enzymatic activation of caspase-8, which in turn activates a downstream caspase cascade in the presence or absence of mitochondrial amplification machinery [10], [11].

Curcumin [1,7-bis(4-hydroxy-3methoxyphenyl)-1,6-heptadien-3,5-dione] is the primary bioactive component isolated from turmeric, a dietary spice made from the rhizome of Curcuma longa [12]. It possesses wide-ranging anti-inflammatory and anticancer properties [13], [14]. The abilities of curcumin to induce apoptosis of cancer cells and to inhibit angiogenesis and cell adhesion contribute to its chemotherapeutic potential in the treatment of cancer [15], [16]. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy in patients with progressive advanced cancers [17]. However, the roles of curcumin in human chondrosarcoma remain largely undefined. To the best of our knowledge, this study is the first to attempt to determine the apoptosis activity of curcumin in human chondrosarcoma cell lines. Our data provide evidence that curcumin reduced cell survival and tumor growth in human chondrosarcoma cells in vitro and in vivo.

Section snippets

Materials

Horseradish peroxidase-conjugated anti-mouse and anti-rabbit IgG, and rabbit polyclonal antibodies specific for Fas, FasL, TRAIL, DR4, DR5, p53, caspase-8, caspase-3, caspase-7, caspase-9, and PARP were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). All other chemicals were obtained from Sigma-Aldrich (St. Louis, MO, USA).

Cell culture

The human chondrosarcoma cell line JJ012 was kindly provided by Dr. Sean P. Scully (University of Miami School of Medicine, Miami, FL, USA). The human

Curcumin induces cell apoptosis in human chondrosarcoma cells

To investigate the potential for curcumin to induce cell death in human chondrosarcoma cells, we first examined the effect of curcumin on cell survival in human chondrosarcoma cells by using the MTT assay. Treatment of cells with curcumin for 24 or 48 h induced cell death in chondrosarcoma (JJ012 and SW1353 cells) but not primary chondrocytes (Fig. 1A). The IC₅₀ values of curcumin for 48 h treatment were 9.1 and 20.8 μM for JJ012 and SW1353 cells, respectively. The anti-cancer activities of

Discussion

Unlike other mesenchymal malignancies, such as osteosarcoma and Ewing's sarcoma, which have dramatic increase in long-term survival with the advent of systemic chemotherapy, chondrosarcoma continues to have a poor prognosis due to absence of an effective adjuvant therapy [25]. The development of novel therapeutic agents targeting the malignant behavior of chondrosarcoma cells is important to improve the prognosis. Curcumin, a major yellow pigment and spice in turmeric and curry, exhibits

Acknowledgments

This work was supported by grants from the National Science Council of Taiwan (NSC99-2320-B-039-003-MY3; NSC100-2320-B-039-028-MY3).

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¹: Equally contributed to this work.

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Curcumin induces cell apoptosis in human chondrosarcoma through extrinsic death receptor pathway

Abstract

Highlights

Introduction

Section snippets

Materials

Cell culture

Curcumin induces cell apoptosis in human chondrosarcoma cells

Discussion

Acknowledgments

J Orthop Res

Curr Opin Struct Biol

Toxicol Lett

Cancer Treat Rev

Biochem Pharmacol

Cancer Lett

Biomaterials

Life Sci

Anal Biochem

Eur J Pharmacol

J Biol Chem

FEBS Lett

Biochem Pharmacol

Cancer Lett

Immunol Today

Biochem Pharmacol

Gynecol Oncol