Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/Reed-Sternberg cells

Abstract

The status of the p53 pathway in classical Hodgkin lymphoma (cHL) remains unclear, and a lack of proven TP53 mutations contrasts with often high expression levels of p53 protein. In this study, we demonstrate that pharmacologic activation of the p53 pathway with the murine double minute 2 (MDM2) antagonist nutlin-3 in Hodgkin lymphoma-derived cell lines leads to effective apoptosis induction and sensitizes the cells to other anticancer drugs. Cells with mutant p53 are resistant to nutlin-3, but sensitive to geldanamycin, a pharmacologic inhibitor of heat shock 90 kDa protein (HSP90), indicating that HSP90 inhibition can induce apoptosis in a p53-independent manner. Conversely, cells with defects in the HSP90/nuclear factor-j B pathway expressing wild-type p53 are more resistant to geldanamycin, but still sensitive to nutlin-3. Our results suggest that selective activation of p53 by MDM2 antagonists as a single agent or in combination with conventional chemotherapeutics and/or inhibitors of p53-independent survival pathways may offer effective treatment options for patients with cHL. Importantly, because nutlins and HSP90 inhibitors are non-genotoxic agents, their use might offer a means to reduce the genotoxic burden of current chemotherapeutic regimens.

Activation of wild-type p53 by MDM2 inhibitors: a new strategy for lymphoma treatment

“…35 These results were confirmed by another team, which reported that the stabilization of p53 by nutlin 3 leads to cell-cycle arrest at the G 1 /S checkpoint and the induction of apoptosis through the expression of Bax or impaired expression of the antiapoptotic protein Bcl-2. 36 Similar studies have been performed in Burkitt's lymphoma (BL), a B-cell lymphoma frequently associated with Epstein-Barr virus (EBV).…”

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

“…[10][11][12] Accordingly, in vitro and in vivo studies have shown that inhibition of Mdm2, a critical negative regulator of p53, by using a recently developed small molecule, nutlin-3a, results in reactivation of the p53 pathway and significant antitumour activity in a variety of solid tumours and some haematologic malignancies harbouring a wild-type (wt) p53 gene. [13][14][15][16][17][18][19][20][21][22][23][24][25] We have shown earlier that most ALK þ ALCL tumours express p53 protein at variable levels and carry a wt p53 gene. 26 In this study, we hypothesized that inhibition of the Mdm2-p53 interaction would result in reactivation of the p53 pathway in ALK þ ALCL cells.…”

Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance

“…[13][14][15][16][17][18][19][20] The p53 transcription factor is a highly complex tumor suppressor gene, which is mutated in approximately 50% human cancers. 2,18,[21][22][23][24] It is often activated by genotoxic stresses, such as those generated upon doxorubicin treatment. p53 has numerous effects on cellular growth: it can induce cell cycle arrest through p21 Cip-1 and it can regulate the Raf/MEK/ ERK pathway by the discoidin domain receptor-1 protein.…”