Oridonin enhances the anticancer activity of NVP-BEZ235 against neuroblastoma cells in vitro and in vivo through autophagy

Abstract

Abstract. The aberrant activation of PI3K/Akt/mTOR signaling pathway plays an important role in the oncogenesis, prognosis and chemotherapy resistance of neuroblastoma. However, NVP-BEZ235, a potent dual PI3K and mTOR inhibitor have not shown beneficial effects on neuroblastoma especially in terms of apoptosis induction as a single agent. We therefore attempted to explore an effective combination regimen to enhance the anticancer activity of NVP-BEZ235. Interestingly, we found that oridonin, a natural biologically active compound extracted from the Chinese medicinal herb Rabdosia rubescens, combined with NVP-BEZ235 markedly induced apoptosis of neuroblastoma cells. Notably, the synergistic activation of the apoptotic pathway was accompanied with enhanced autophagy as evidenced by significant decreased p62 expression as well as upregulated conversion of LC3-II. Suppression of the Beclin-1, a core component of the autophagy machinery, by means of shRNA resulted in diminished synergistic antitumor effect. Furthermore, the co-treatment with oridonin and NVP-BEZ235 was also much more effective than either agent alone in inhibiting the growth of neuroblastoma xenografts and in inducing tumor cells apoptosis. Taken together, our results suggest that the combination of NVP-BEZ235 and oridonin is a novel and potential strategy for neuroblastoma therapy.

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Hara [543]. As an orally available drug, oridonin is demonstrated to have anti-cancer activities in multiple cancers over the past decades, including leukemia, lymphoma, osteosarcoma, myeloma, uveal melanoma, neuroblastoma, hepatocellular, laryngeal, esophageal, and oral squamous cell carcinoma, lung, colorectal, breast, gastric, pancreatic, and prostatic cancers [543][544][545][546][547][548][549][550][551][552][553][554][555][556][557][558]. The anti-cancer effects of oridonin are shown in many aspects, including the induction of cell apoptosis, autophagy, cell cycle arrest, and the suppression of angiogenesis, cell migration, invasion and adhesion [554,[559][560][561][562][563][564].…”

“…Oridonin is also shown to induce autophagy in many cancer cells, which is associated positively or negatively with apoptosis. It induces autophagy to mediate apoptosis in human NSCLC A549 and neuroblastoma SHSY-5Y cells [558,568]. On the other hand, autophagy provides a protective role against oridonin-induced apoptosis, as autophagy inhibitor enhances oridonin-induced apoptosis in human cervical carcinoma HeLa, multiple myeloma RPMI 8266, laryngeal cancer HEp-2 and Tu212, and epidermoid carcinoma A-431 cells [569][570][571][572].…”

“…The combination of γ-tocotrienol and oridonin exerts synergistic anti-cancer effects in murine + SA mammary adenocarcinoma epithelial cells, which are mainly through the induction of autophagy [589]. Moreover, oridonin can enhance the pro-apoptotic activity of NVP-BEZ235 in human neuroblastoma SHSY-5Y and SK-N-MC cells through autophagy [558], whilst the combination of oridonin and cetuximab exhibits potent pro-apoptotic effect in human laryngeal cancer HEp-2 and Tu212 cells [572].…”

Oridonin induces Mdm2‐p60 to promote p53‐mediated apoptosis and cell cycle arrest in neuroblastoma

“…9,11,12 Oridonin is a kind of active diterpenoid derived from traditional Chinese medicine. 13 It has a wide range of biological effects, such as anticancer, antibacterial, and anti-inflammatory activities. 14 And, many oridonin derivatives have been designed and synthesized.…”

“…Our previous studies have shown that oridonin enhances the anticancer activity of NVP-BEZ235 against NB cells through autophagy. 13 And, it has also been proved that oridonin can also generate ROS to sensitize NB cells to TRAILinduced apoptosis. 26 At present, we investigate the effects of oridonin on NB cells and further explore the detailed molecular mechanisms.…”