Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5

Abstract

Acute myeloid leukemia (AML) cells are relatively resistant to tumor necrosis factor ␣-related apoptosis-inducing ligand (TRAIL). We previously reported that triptolide, a potent anticancer agent from a Chinese herb, decreases XIAP in leukemic cells. We evaluated the combination of triptolide and TRAIL and found synergistic promotion of apoptosis in AML cells. XIAP-overexpressing U937 cells (U937XIAP) were more resistant to TRAIL than U937neo cells, and inhibition of XIAP with the small-molecule inhibitor 1396-11 enhanced TRAIL-induced apoptosis, implying XIAP as a resistance factor in AML. Furthermore, triptolide increased DR5 levels in OCI-AML3, while the DR5 increase was blunted in p53-knockdown OCI-AML3 and p53-mutated U937 cells, confirming a role for p53 in the regulation of DR5. In support of this finding, disruption of MDM2-p53 binding with subsequent increase in p53 levels by nutlin3a increased DR5 levels and sensitized OCI-AML3 cells to TRAIL. The combination of 1396-11 plus nutlin3a plus TRAIL was more effective than either the 1396-11 and TRAIL or nutlin3a and TRAIL combinations in OCI-AML3 cells, further supporting the role of triptolide as a sensitizer to TRAILinduced apoptosis in part by independent modulation of XIAP expression and p53 signaling. Thus, the combination of triptolide and TRAIL may provide a novel strategy for treating AML by overcoming critical mechanisms of apoptosis resistance.

The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53

“…33,46 Our data provide evidence that such therapeutic strategies can be improved by incorporation of agents such as nutlin-3a, in agreement with others. 47,48 Recent studies have shown that nutlin-3a, at very high concentrations, usually 420-30 mM, can inhibit the growth of cancer cells with deleted p53, or harbouring a nonfunctional, mt p53 gene, although the exact mechanism is incompletely understood. 35,36 It seems, depending on the in vitro system, that activation of other partners of Mdm2, including p73 or E2F1, may be involved in this phenomenon.…”

The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine

“…7,8,16,[21][22][23] Importantly, treatment with Ara-C alone significantly increased the transcription of BCL2 and XIAP (P ¼ 0.0002 and P ¼ 0.0028, respectively). Both of these genes have been implicated in drug resistance mechanisms in AML [24][25][26][27] and so their transcriptional activation may limit the apoptotic response to Ara-C. Remarkably, the combination of SNS-032 and Ara-C resulted in decreased MCL1 expression Figure 5 The existence of synergy between SNS-032 and Ara-C was determined using a ratio of 1 SNS-032 to 1.9 Ara-C and treating 25 primary AML samples to these two agents separately and in combination for 48 h. The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML E Walsby et al (P ¼ 0.021) and decreased expression of XIAP (Po0.0001) and BCL2 (P ¼ 0.0002), providing a rationale for at least one mechanism for the synergy seen with these agents.…”

Enhanced Anti-tumor Efficacy of Aspirin Combined with Triptolide in Cervical Cancer Cells

“…Newly report shown that triptolide have the potential to suppress the proliferation of human tumors in vitro (Zhu et al, 2009;Borja-Cacho et al, 2010;Clawson et al, 2010;Zhao et al, 2010;Lu et al, 2011). It is worth noting that triptolide possess side effects in both immunosuppressive and antifertility activities (Carter et al, 2008;Westfall et al, 2008;Yang et al, 2008;Chen et al, 2009). In this, the role of triptolide in cancer treatment needs to be reconsidered.…”

“…Another widely used drug, triptolide, the major composition extracted from the Chinese herb Tripteryglum wilfordii Hook.f, has now been shown that it can inhibit tumor growth (Clawson et al, 2010;Zhao et al, 2010;Lu et al, 2011;Li et al, 2012;Zhu et al, 2012;Huang et al, 2013;Tan et al, 2013). However, triptolide still have side effects such as immunosuppressive and antifertility (Carter et al, 2008;Westfall et al, 2008;Yang et al, 2008;Chen et al, 2009;Zhu et al, 2009;Borja-Cacho et al, 2010).…”