Oridonin synergizes with Nutlin-3 in osteosarcoma cells by modulating the levels of multiple Bcl-2 family proteins

Abstract

The small-molecule inhibitors of p53-murine double minute 2 interaction, such as Nutlin-3, are effective against cancers bearing wild-type p53. However, murine double minute 2 inhibitors often are unable to completely eliminate solid tumor cells. To address this issue, we investigated the anticancer effects of Nutlin-3 in combination with Oridonin in osteosarcoma cells. We found that Oridonin at sub-toxic concentrations synergistically enhanced Nutlin-3-mediated cell viability inhibition in wild-type p53 U2OS and SJSA-1, but not in p53-mutant MNNG/HOS and in null-p53 Saos-2 osteosarcoma cell lines. Importantly, in the presence of Oridonin, Nutlin-3 could completely abolish cell viability in the wild-type p53 osteosarcoma cell lines. Western blotting analysis showed that Oridonin treatment rapidly and distinctly increased the levels of all three forms of Bim and also markedly reduced the levels of Bcl-2 and Bcl-xl in osteosarcoma cells. Western blotting analysis further showed that Oridonin considerably enhanced Nutlin-3-triggered activation of caspases-9 and -3 and poly(ADP-ribose) polymerase cleavage. Flow cytometry assay showed that Oridonin significantly enhanced Nutlin-3-mediated apoptosis in wild-type p53 osteosarcoma cells. Overall, our results suggest that the combined treatment of Nutlin-3 plus Oridonin may offer a novel therapeutic strategy for osteosarcoma.

MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53

“…Unsurprisingly, when HCT116 cells were measured for viability following A1874 incubation, the reduction in viability was striking compared to that due to either of the individual ligand components; and even synergistic compared to the sum of their effects.. Enhanced effects has been demonstrated between nutlins combined with other anti-cancer drugs (30,31,55), however such studies to date have relied on protein inhibition rather than PROTAC-mediated protein degradation.…”

“…However, in light of the potential wide-ranging amenability of E3 ligases for repurposing into resources for PROTAC-mediated protein degradation, we reasoned that renewed effort concerning nutlin-based PROTACs was worthwhile considering that, among the E3 ligases currently used for PROTACs, MDM2 stands out in that its endogenous substrate, the tumor suppressor p53, plays a crucial tumor suppressor role. Indeed, the ability to manipulate p53 levels using nutlins holds therapeutic promise in the field for cancer treatment (30,31).…”

Biocompatible Fe-Based Micropore Metal-Organic Frameworks as Sustained-Release Anticancer Drug Carriers

“…Oridonin (Ori) is an ent -kaurene diterpenoid compound ( Figure 1 a), extracted from the medicinal herb Rabdosia rubescenes [ 2 ]. Past studies found that oridonin has conspicuous anti-tumor activity in many types of human cancer, such as triple-negative breast cancer cells [ 3 , 4 ], osteosarcoma cells [ 5 ], human hepatoma cells [ 6 ], prostate cancer cells [ 7 ], and myeloma cells [ 8 ]. Therefore, it has attracted wide attention.…”

NLRP1 and NLRP3 inflammasomes as a new approach to skin carcinogenesis (Review)

“…Great hope for revolutions in treatment rest on oridonin (ORI), one of the most important active Chinese medicinal components isolated from Rabdosia rubescens, which has been shown to be a potent anti-metastatic agent. Notably, oridonin shows a broad-spectrum of anti-proliferative and anti-cancer activities in various types of tumor (63)(64)(65)(66)(67)(68) as well as in melanoma (69,70). Wang et al (69) indicated that ORI induces human melanoma A375-S2 cell death (69).…”