Costunolide enhances doxorubicin-induced apoptosis in prostate cancer cells via activated mitogen-activated protein kinases and generation of reactive oxygen species

Abstract

The management of castration-resistant prostate cancer (CRPC) is challenging, attributable to a lack of efficacious therapies. Chemotherapy is one of the most important treatments for CRPC. Doxorubicin has been extensively used in many different tumors and is often combined with other drugs to enhance effects and reduce toxicity. Costunolide is a natural sesquiterpene lactone with anti-cancer properties. In this study, we first demonstrated that the combination of costunolide and doxorubicin induced apoptosis significantly more than either drug alone in prostate cancer cell lines. Costunolide combined with doxorubicin induced mitochondria-mediated apoptosis through a loss of mitochondrial membrane potential and modulation of Bcl-2 family proteins. We found that this drug combination significantly increased the production of reactive oxygen species (ROS), as well as phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases, which play upstream roles in mitochondria-mediated apoptosis. Further studies showed that N-acetyl cysteine blocked JNK and p38 phosphorylation, suggesting that ROS were upstream activators of JNK and p38. However, a JNK inhibitor, but not a p38 inhibitor, blocked the increase in ROS observed in cells treated with a combination of costunolide and doxorubicin, suggesting that ROS and JNK could activate each other. In vivo, inhibition of tumor growth and induction of apoptosis were greater in mice treated with the costunolide and doxorubicin combination than in mice treated with either drug alone, without an increase in toxicity. Therefore, we suggested that costunolide in combination with doxorubicin was a new potential chemotherapeutic strategy for treating prostate cancer.

Costunolide induces mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells

“…Reactive oxygen species (ROS) production induced by costunolide may be the important intermediate link of mitochondrial apoptosis. Costunolide has the potential to activate extrinsic pathway or endoplasmic reticulum stress pathway [21][22][23]. Our research group will be further to explore the mechanisms of costunolide via signaling pathway (such as p53, NF-κB and Wnt/β-catenin signaling pathway) and even find the specific molecular target [6,7].…”

Flavokawain B and Doxorubicin Work Synergistically to Impede the Propagation of Gastric Cancer Cells via ROS-Mediated Apoptosis and Autophagy Pathways

“…The chalcone FKB induces ROS-mediated autophagic cell death (not apoptosis) in AGS cells [27]. Doxorubicin induces ROS-mediated apoptosis in various cancer cells [28,29]. The AGS cells were exposed to various concentrations of FKB 1.5-5 µg/mL and 0.5 µg/mL of doxorubicin for 24 h, respectively, to look into any potential effects as to the propagation and survival of ASG cells.…”

“…The chalcone FKB induces (ROS-mediated) autophagy cell death (not apoptosis) in AGS cells [27]. It has also been reported that doxorubicin induces apoptosis in various cancer cells, which is known to be mediated through ROS [28,29]. Therefore, this study was aimed to investigate the synergistic effects of FKB and doxorubicin combination treatment on AGS cells and the role of apoptosis and autophagy mechanisms were elucidated.…”

Mitochondrial Dysfunction Associated with Doxorubicin

“…While ERK1/2 predominantly operates cell proliferation, JNK and p38 participate in cell death pathways. DOX has been shown to kill prostate cancer cells by phosphorylation of p38 and JNK [74]. One of the MAPKs is p38, which has a pivotal role in cell growth, apoptosis, and inflammation.…”