Chronic lymphocytic leukemia and treatment resistance in cancer: The role of the p53 pathway

Zenz, Thorsten; Benner, Axel; Döhner, Hartmut; Stilgenbauer, Stephan

doi:10.4161/cc.7.24.7245

Cited by 71 publications

(60 citation statements)

References 21 publications

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“…The tumor suppressor protein p53, often mutated in human tumors, regulates apoptosis and cell survival upon DNA damage (39)(40)(41)(42). Tumor cells with p53 mutations are often resistant to cytotoxic drugs, such as cisplatin (43)(44)(45). Given that PC-3 cells do not express tumor suppressor p53, our data indicate that the cytotoxic effects of PCNA-I1 were likely mediated by both p53-dependent and -independent pathways.…”

Section: Discussionmentioning

confidence: 77%

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Dillehay

Dong

2014

Molecular Cancer Therapeutics

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Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 is most potent. The purposes of this study were to further investigate the effects of targeting PCNA chromatin association on DNA damage and cytotoxicity and to evaluate the therapeutic potential of PCNA-I1 against tumors in mice. Given the important roles of tumor suppressor p53 in regulating sensitivity of tumor cells to chemotherapeutics, we performed studies in two human prostate cancer cell lines differing in p53 expression: LNCaP cells (wild-type p53) and PC-3 cells (p53-null). PCNA-I1 induced DNA damage and apoptosis in both LNCaP and PC-3 cells and enhanced DNA damage and apoptosis triggered by cisplatin. PCNA-I1 also induced autophagy in PC-3 cells. A short-term pretreatment with PCNA-I1 reduced colony formation by 50% in both cell lines. These data suggest that, unlike many other cytotoxic drugs, the effects of PCNA-I1 on tumor cells do not depend on expression of p53. Intravenous administrations of PCNA-I1 significantly retarded growth of LNCaP tumors of in nude mice without causing detectable effects on mouse body weight and hematology profiles. These data provide proof of concept that targeting PCNA chromatin association could be a novel and effective therapeutic approach for treatment of cancer. Mol Cancer Ther; 13(12); 2817-26. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 77%

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Dillehay

Dong

2014

Molecular Cancer Therapeutics

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“…Loss of genes encoding p53 or its upstream activator Atm identifies a particularly poor prognosis subset of patients, 39,40 resulting in part from the dependence of conventional cytotoxic agents on the p53 pathway. Clinical trial evidence to date indicates that patients with genetic abnormalities impacting on the p53 pathway need treatment with agents that can act independently of this pathway.…”

Section: Therapeutic Strategies For Cll Patients With a Dysfunctionalmentioning

confidence: 99%

“…Deletions of chromosomes 17p or 11q, the locations of the p53 and ATM genes respectively, identify particularly aggressive forms of the malignancy. 39,40 These deletions are frequently, but not invariably, associated with mutational inactivation of the respective remaining allele, resulting in comprehensive loss of p53-dependent apoptotic responses to DNA-damaging agents. 41,42 A detailed microarray analysis revealed subtle differences in the transcriptional response to DNA damage between CLL cells with lesions in the p53 or ATM genes.…”

Section: Transcriptional Targets Of P53mentioning

confidence: 99%

p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies

2011

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The p53 tumor suppressor protein has a key role in the induction of apoptosis of chronic lymphocytic leukemia (CLL) cells. Abnormalities within the p53 pathway identify a subset of patients with a poor prognosis. This review describes recent advances in understanding the mechanisms that regulate p53 levels and the role of p53 in the control of the cell cycle and of apoptosis. The classical model of p53-mediated apoptosis emphasizes the transcriptional activation of proapoptotic genes. In contrast, a novel model emphasizes p53's non-transcriptional actions as the major route of apoptosis induction, whereas its transcriptional arm predominantly upregulates antiapoptotic genes, thus providing a negative feedback mechanism that limits apoptosis. Further studies have identified the Notch pathway as a candidate p53-induced antiapoptotic mechanism. In contrast to the classical model, the novel model predicts that pharmacological inhibition of p53's transcriptional function or of the Notch signaling pathway will augment apoptosis induction by cytotoxic agents. Therapeutic strategies based on the novel model, which we review here for the first time, may significantly augment the antitumor actions of cytotoxic agents in CLL and in other malignancies.

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“…Impaired p53 function through mutation and/or deletion is the best-characterized factor associated with chemoresistance in CLL. 16,17 However, a considerable number (Ͼ 50%) of refractory CLL patients do not exhibit TP53 mutations or 17p deletion. 18 Deregulation of other components of the DNA-damage response and repair pathways might be involved in CLL chemoresistance; for example, ATM, DNA-PK (DNA-dependent protein kinase), the tumor suppressors p16 INK4a and p14 ARF , and microRNA-34a.…”

Section: Introductionmentioning

confidence: 99%

DNA damage–induced transcriptional program in CLL: biological and diagnostic implications for functional p53 testing

Mohr

Helfrich

Fuge

et al. 2011

Blood

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The DNA damage pathway plays a central role in chemoresistance in chronic lymphocytic leukemia (CLL), as indicated by the prognostic impact of TP53 and ATM loss/ mutations. We investigated the function of the p53 axis in primary CLL samples by studying p53 and p21 responses to irradiation by FACS and RT-PCR. We observed a distinct response pattern for most cases with a 17p deletion (n ‫؍‬ 16) or a sole TP53 mutation (n ‫؍‬ 8), but not all cases with a p53 aberration were detected based on a number of different assays used. Samples with a small clone with a TP53 mutation remained undetected in all assays. Only 1 of 123 cases showed high expression of p53, which is suggestive of p53 aberration without proof of mutation of TP53. Samples with an 11q deletion showed a heterogeneous response, with only 13 of 30 showing an abnormal response based on cutoff. Nevertheless, the overall induction of p53 and p21 was impaired, suggesting a gene-dosage effect for ATM in the 11q-deleted samples. The detectability of p53 defects is influenced by clonal heterogeneity and sample purity. Functional assays of p53 defects will detect a small number of cases not detectable by FISH or TP53 mutational analysis. The clinical utility of functional p53 testing will need to be derived from clinical trials. (Blood. 2011;117(5): 1622-1632)

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Chronic lymphocytic leukemia and treatment resistance in cancer: The role of the p53 pathway

Cited by 71 publications

References 21 publications

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies

DNA damage–induced transcriptional program in CLL: biological and diagnostic implications for functional p53 testing

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