Apogossypolone induces apoptosis and autophagy in nasopharyngeal carcinoma cells in an in vitro and in vivo study

Abstract

Nasopharyngeal carcinoma (NPC) has a high incidence and mortality rate, particularly in Southern China. Apogossypolone (ApoG2) is a novel derivative of gossypol with antitumor activity and less toxicity. The human NPC CNE-2 cell line was studied in the in vitro model; whilst 4 week-old male nude mice (BALB/c-nu) were inoculated subcutaneously with CNE-2 cells, and xenograft tumors were studied in the in vivo model. Graded concentrations of ApoG2 were used in treatment studies. In ApoG2-treated and control in vitro and in vivo tumor cells, cell apoptosis, and autophagy were evaluated and quantified using fluorescent and transmission electron microscopy and flow cytometry. Hoechst-33258 fluorescence staining was used to evaluate apoptosis in treated and non-treated cell culture and xenograft NPC cells. Western blotting was performed on lysed tumor cells using primary antibodies to B-cell lymphoma-2 (Bcl-2), beclin-1, and β-actin, and flow cytometry results indicated cell apoptosis rates of 3.90±0.34 and 19.52±1.18% in the control and ApoG2-treated cells, respectively (F=485.294, P<0.001). Western blot analysis showed that ApoG2 significantly decreased expression of the Bcl-2 protein in CNE-2 cells, when compared with control cells (F=68.909, P=0.001) and flow cytometry showed cell autophagy rates of 0.92±3.10% of control cells compared with 28.24±7.35% of ApoG2-treated cells (F=31.035, P=0.003). ApoG2 treatment significantly increased beclin-1 protein expression in CNE-2 cells (F=497.906, P<0.001). ApoG2 treatment inhibited NPC xenograft tumor growth by 65.49% (P<0.05). In conclusion, these results support a role for ApoG2 in inhibiting the growth of human NPC cells by inducing apoptosis and autophagy. Future controlled clinical studies could be planned, to define safety, efficacy and dosing regimens for ApoG2 as a potential treatment for patients with NPC.

Apogossypolone Inhibits Cell Proliferation and Epithelial-Mesenchymal Transition in Cervical Cancer via Activating DKK3

“…Similar to our data, ApoG2 could effectively inhibit proliferation of NPC cells that expressed antiapoptotic Bcl-2 family proteins at a high level(19). The report by Zheng et al(38) further supported the suppressive role of ApoG2 on the growth of human NPC cells by inducing apoptosis and autophagy. ApoG2 could induce apoptosis through up-regulation of Bax and down-regulation of Bcl-2, increasing reactive oxygen species (ROS) levels, inducing cytochrome C release and cleaving caspase proteins(39).…”

Effect of colony‐stimulating factor‐1 receptor overexpression on the growth of nasopharyngeal carcinoma xenografts in nude mice and its mechanism of action

“…Zheng et al . reported that the regulation of gossypol derivative ApoG2 can reduce the expression of Bcl‐2, and promote apoptosis and autophagy in nasopharyngeal carcinoma CNE2 cells, thus inhibiting tumor growth . Song et al .…”

“…Bcl-2, and promote apoptosis and autophagy in nasopharyngeal carcinoma CNE2 cells, thus inhibiting tumor growth. 18 Song et al observed that autophagy is responsible for paclitaxel resistance seen in nasopharyngeal carcinoma cells. 19 Makowska et al 20 found that the autophagy levels of NPC cell CNE-2R are negatively correlated with apoptosis and radiation resistance.…”

Insights into Novel Drugs Targeting Bcl-2 protein as Potential Anti-cancer Agents

“…Nonetheless, despite it is considered to be a favorable drug in the therapy of cancer and reaching clinical human trials, downside with gossypol was found, because of its structure which contain two aldehydic groups that linked with toxicity and as potential targets for another proteins (Baggstrom et al, 2011). Therefore, derivatives of gossypol arisen such as apo gossypol, produced by eliminating the two aldehydic groups ,for which better activity in leukemias, liver cancer ,nasopharyngeal carcinoma cells, breast cancer, prostate cancer and pancreatic cancer has been stated; furthermost significantly, it has lesser toxicity than that of gossypol (Zheng et al, 2017).…”