Loss of p53 function impairs apoptosis induced by DNA-damaging agents used for cancer therapy. Here, we examined the effect of the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) on doxorubicin-induced apoptosis in lymphoma. We aimed to establish the optimal schedule for administration of both drugs in combination and the molecular basis for their interaction.
Isogenic lymphoblastoid and nonisogenic lymphoma cell lines differing in p53 status were exposed to each drug or combination. Drug effects were examined using Annexin V, active caspase-3, cell cycle, and cytotoxicity assays. Synergy was evaluated by median effect/combination index. Protein expression and kinase inhibition provided insight into the molecular mechanisms of drug interaction.
Presence of mutant p53 conferred increased survival to single agents. Nevertheless, DMAG showed synergistic toxicity with doxorubicin independently of p53 status. Synergy required exposure to doxorubicin before DMAG. DMAG-mediated down-regulation of CHK1, a known HSP90 client, forced doxorubicin-treated cells into premature mitosis followed by apoptosis. A CHK1 inhibitor, SB-218078, reproduced the effect of DMAG. Administration of DMAG before doxorubicin resulted in G1-S arrest and protection from apoptosis, leading to additive or antagonistic interactions that were exacerbated by p53 mutation.
Administration of DMAG to doxorubicin-primed cells induced premature mitosis and had a synergistic effect on apoptosis regardless of p53 status. These observations provide a rationale for prospective clinical trials and stress the need to consider schedule of exposure as a critical determinant of the overall response when DMAG is combined with chemotherapeutic agents for the treatment of patients with relapsed/refractory disease.
"However, this could be due to activation of wild-type p53 and consequent p53-dependent apoptosis. Further research has shown a synergistic effect between 17-DMAG and Doxorubicin, demonstrating a sensitisation of p53 mutated cells to Doxorubicin-induced cell death (Robles et al. 2006). HSPC1 chaperones a broad array of protein kinases involved in signal transduction pathways including phosphorylated Akt, Lyn, B-Raf and IκK (Broemer et al. 2004; da Rocha Dias et al. 2005; Sato et al. 2000; Trentin et al. 2011). "
"Using DMAG-17, a specific HSP90 inhibitor to block its activity, we observed that HSP90 inhibition significantly enhanced Lexa treatment-induced apoptotic cell death (Fig. 7B and 7D) and ROS production (Fig. 7C and 7D) in HCC cells, suggesting HSP90 may be involved in Lexa-induced ROS generation. It has also been reported that DMAG-17 can induce apoptosis in tumor cells through down-regulating IKKs, Mcl-1, and survivin expression . However, in this study, apoptosis assays indicated that HCC cells are insensitive to DMAG-17 single treatment (Fig.7B and 7D). "
[Show abstract][Hide abstract] ABSTRACT: This study aims to investigate apoptosis induced by lexatumumab (Lexa) in hepatocellular carcinoma (HCC) cells. We assessed the sensitivity of HCC cell lines and normal human hepatocytes to Lexa and explored the sensitization of HCC cells to Lexa-induced apoptosis by cycloheximide (CHX). Our data indicated that CHX sensitized HCC cell lines to Lexa-induced apoptosis, whereas treatment using solely CHX or Lexa was ineffective. The sequential treatment of CHX followed by Lexa dramatically induced caspase-dependent apoptosis in HCC cells and had synergistically increased intracellular rates of reactive oxygen species (ROS). Additionally, when ROS production was blocked by N-acetyl-L-cysteine (NAC), HCC cells were protected against Lexa and CHX combination treatment-induced apoptosis. ROS generation induced by combination treatment of Lexa and CHX triggered pro-apoptotic protein Bax oligomerization, conformation change, and translocation to mitochondria, which resulted in the release of cytochrome c and subsequent cell death. Furthermore, HSP90 was involved in mediating Lexa and CHX combination treatment-induced ROS increase and apoptotic death. More importantly, we observed that combination treatment of Lexa and CHX did not cause apoptotic toxicity in normal human primary hepatocytes. These results suggest that Lexa and CHX combination treatment merits investigation for the development of therapies for patients with HCC.
PLoS ONE 02/2011; 6(2):e16966. DOI:10.1371/journal.pone.0016966 · 3.23 Impact Factor
"A combination of 17-DMAG with arsenic trioxide has emerged as a promising therapeutic combination since they synergize to induce apoptosis and mitotic arrest in leukemic cells . Combined therapies to overcome 17-AAG dependence on p53 status might be also interesting as shown with doxorubicin in lymphoma cells . Hyperacetylation of HSP90 by HDAC inhibitors increased its binding to 17-AAG and its subsequent anti-leukemic activity . "
[Show abstract][Hide abstract] ABSTRACT: Heat shock proteins (HSPs) HSP27, HSP70 and HSP90 are powerful chaperones. Their expression is induced in response to a wide variety of physiological and environmental insults including anti-cancer chemotherapy, thus allowing the cell to survive to lethal conditions. Different functions of HSPs have been described to account for their cytoprotective function, including their role as molecular chaperones as they play a central role in the correct folding of misfolded proteins, but also their anti-apoptotic properties. HSPs are often overexpressed in cancer cells and this constitutive expression is necessary for cancer cells' survival. HSPs may have oncogene-like functions and likewise mediate "non-oncogene addiction" of stressed tumor cells that must adapt to a hostile microenvironment, thereby becoming dependent for their survival on HSPs. HSP-targeting drugs have therefore emerged as potential anti-cancer agents. This review describes the different molecules and approaches being used or proposed in cancer therapy based on the in inhibition of HSP90, HSP70 and HSP27.
Cancer letters 11/2010; 332(2). DOI:10.1016/j.canlet.2010.10.014 · 5.62 Impact Factor
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