Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs

Abstract

IntroductionB chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5 ϩ CD19 ϩ B-lymphoid cells. Although CLL cells proliferate slowly, defective apoptosis results in progressive accumulation of the malignant clone. [1][2][3] The clinical course of CLL is highly variable. Although a proportion of patients survive for extended periods without the need for clinical intervention, others undergo rapid disease progression and require aggressive treatment. Recent studies have established that a subset of patients with CLL with unmutated immunoglobulin heavy chain variable (IgV H ) genes have an inferior clinical outcome compared to the subset with mutated IgV H genes. 4,5 Furthermore, expression of the protein tyrosine kinase ZAP-70 correlates well with an unmutated IgV H status, providing an accessible alternative criterion for the management of patients with CLL. [6][7][8] There is an urgent need to develop novel protocols for the treatment patients with a poor prognosis identified by IgV H mutation analysis or ZAP-70 expression.For many years, the nitrogen mustard chlorambucil has been the drug of choice in CLL. More recently, the nucleoside analog fludarabine has proved useful, especially for the treatment of patients who fail to respond to chlorambucil. 9 Although high remission rates have been achieved using this drug, 10 myelosuppression has proved to be a critical dose-limiting factor. 11 Fludarabine is also highly toxic to T lymphocytes and results in prolonged depression of CD4 ϩ T cells, increasing the risk of opportunistic infections. 11,12 Therefore, there has been considerable interest in identifying novel drugs that induce CLL apoptosis with greater selectivity. [13][14][15][16][17][18][19][20][21][22][23][24] Deletion of the p53 tumor suppressor gene, whose protein product is a key mediator of drug-induced apoptosis, predicts a poor response to cytotoxic drugs. 25,26 However, even CLL cells harboring intact p53 genes may be defective in p53-mediated apoptosis, resulting from the inactivation of the ATM protein kinase pathway, 27-30 which links DNA damage induction to p53 up-regulation. Because of the limitations of existing therapeutic options, [9][10][11][12][25][26][27][28][29][30] it is important to evaluate drugs that induce apoptosis of CLL cells via actions on novel cellular targets. 24 Optimal new drugs would display a high degree of selectivity for the malignant cells while sparing hematopoietic progenitors and T lymphocytes. Further advantageous characteristics include a p53-independent mode of action and synergistic actions with conventional cytotoxic drugs.The ansamycin antibiotics geldanamycin (GA) and herbimycin A (HMA) have attracted interest as potential anticancer agents. 31,32 These drugs target the adenosine triphosphate (ATP)-binding pocket of the cytosolic chaperone heat shock protein 90 (Hsp90). 33 Hsp90 ensures maintenance of the correctly folded conformation of a range of client proteins involved in signal transduction, including Akt, Raf-1, Erb B2, and...

Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells

“…An alternative explanation for the cytotoxicity of Hsp90 inhibition in all CLL samples is that cell death resulted from the loss of survival signals consequent to depletion of Akt, as proposed by Jones DT et al (2004a). Thus, Akt is thought to play a key role in maintaining the viability of CLL cells in vivo independently of any effect on the MDM2-p53 pathway (Jones et al, 2003).…”

Network-based analysis of calcium-binding protein genes identifies Grp94 as a target in human oral carcinogenesis

“…Interestingly, a recent study has shown that inhibition of Grp94 expression by geldanamycin in chronic lymphocytic leukaemia cells induces apoptosis with modest cytoprotective effects of primary haematopoietic progenitors from normal bone marrow (Jones et al, 2004). In addition, targeting cancer cells with an antisense or RNAi procedure against Grp94 has shown increased chemosensitivity or radiosensitivity (Reddy et al, 1999;Kubota et al, 2005).…”

Hsp90-inhibitor geldanamycin abrogates G2 arrest in p53-negative leukemia cell lines through the depletion of Chk1

“…Because these pathways are constitutively activated in many tumor cells, GM is expected to have a potent antitumor activity (Gorre et al, 2002;Minami et al, 2002;Bisht et al, 2003). GM and its less toxic derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) have been reported to inhibit tumor cell growth by inducing apoptosis and, in certain cell types, differentiation (Mu¨nster et al, 2001;Jones et al, 2004;Mitsiades et al, 2006). GM is reported to enhance tumor cell sensitivity to various cytotoxic agents and ionizing radiation through the inhibition of nuclear factor (NF)-kB activation and its downstream survival signals (Lewis et al, 2000;Broemer et al, 2004).…”