Ovarian cancer is the most lethal gynecologic cancer among women in the developed world. DDP-based chemotherapy remains the first-line treatment for this type of cancer. Although the majority of patients are initially sensitive to DDP chemotherapy, nearly 80–90% of those patients will eventually develop resistance to this treatment, leading to acquired DDP resistance and causing high mortality. Therefore, molecular targeted therapies or common low-cost drugs that can be combined with conventional treatments are urgently needed.
CAM is a well-known macrolide antibiotic traditionally used for various types of bacterial infections. Recently, extensive research has demonstrated that CAM may act as an anti-inflammatory agent rather than an antibacterial one [
19]. Moreover, CAM may not only play a role in the treatment of various tumors, but it may also potentiate the antitumor activity of many kinds of cytotoxic drugs as well in vitro and in vivo [
8,
9,
20]. In the present study, we showed that CAM treatment alone could induce apoptosis in ovarian cancer cells, attenuate ovarian tumor growth and function synergistically with DDP to potentiate antitumor activity. In vitro, we observed that the apoptosis rates of the two ovarian cancer cell lines were increased after CAM administration in a dose-dependent manner. In addition, the apoptosis rates were significantly increased when CAM was administered in combination with a conventional chemotherapy agent, DDP. In vivo, a subcutaneous xenograft model indicated that CAM could slightly inhibit the tumor growth, but this finding was not statistically significant (CAM group vs vehicle,
P = 0.1145); however, the tumor weight was lower than that of the vehicle group, which was a statistically significant difference (CAM group vs vehicle,
P = 0.0309). This conflict may be due to measuring error while recording each tumor size. More notably, the tumor volumes and weights were significantly lower after combined treatment than with DDP treatment alone, and this result was statistically significant. Mechanistically, we found that treatment with CAM and DDP led to increased ROS levels, which were mainly generated in mitochondria, due to decreased expression of intracellular antioxidant enzymes. This phenomenon was validated both in vitro and in vivo. Previous studies have demonstrated that multiple mechanisms may underlie the antitumor activity of CAM, and no consistent conclusion has been reached. A study performed by Qiao Ai-Min et al. demonstrated that CAM-induced apoptosis in human cervical cancer HeLa cells was activated through the mitochondrial-mediated apoptotic pathway that is involved in cytochrome c release and the activation of caspase-9 and caspase-3 [
15]. Peng YC et al. reported that CAM administration could inhibit the NF-κB pathway in gastric epithelial cells, as NF-κB is a critical transcription factor that regulates inflammatory responses and innate immunity [
21]. In non-small-cell lung cancer (NSCLC), Mikasa et al. found that NSCLC patients who received CAM treatment (200 mg b.i.d.) showed better conditions and prolonged survival times compared to those not treated with CAM due to reduced serum IL-6 levels after treatment [
22,
23]. Aside from influencing secretory factors and cytokines, CAM affects the VEGF pathway [
9]. Other research has suggested that antitumor activity in NSCLC patients might be partly mediated via the modulation of ERK1/2 by CAM administration [
24]. Miki Nakamura et al. demonstrated that CAM augmented the antitumor activity of thalidomide against multiple myeloma (MM) cells through autophagy attenuation [
7], and it has been reported that CAM enhanced bortezomib-induced cytotoxicity via ER stress-mediated CHOP induction in breast cancer cells [
8]. ROS-mediated induction of apoptosis and protection from radiation-induced lung injury were also reported [
10,
16]. To the best of our knowledge, ours is the first study to investigate the synergistic effects of CAM with DDP to promote the apoptosis of ovarian neoplasms, which was mediated by inducing an increase in ROS in vitro and in vivo.
Our study demonstrated for the first time that CAM augments DDP response when administered in combination via an ROS-mediated synergistic effect. However, this study still has several limitations. Other chemotherapeutic agents such as taxol have not been included in our current study. Moreover, in our study, CAM was administered simultaneously to induce tumor cell apoptosis, and whether treatment before or after chemotherapy affords similar effects has yet to be studied. Thus, further study investigating the use of this drug combination and role of different mechanisms in vitro and in vivo are greatly warranted.