Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma

Marzo, Domenico Di; Forte, Iris Maria; Indovina, Paola; Gennaro, Elena Di; Rizzo, Valeria; Giorgi, Francesca De; Mattioli, Eliseo; Iannuzzi, Carmelina Antonella; Budillon, Alfredo; Giordano, Antonio; Pentimalli, Francesca

doi:10.4161/cc.27546

Cited by 34 publications

(30 citation statements)

References 54 publications

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“…RITA inhibited growth of medulloblastoma tumor xenografts and significantly prolonged mouse survival without causing visible signs of toxicity in the animals. These findings were consistent with previous studies of RITA in xenograft models of colon carcinoma, neuroblastoma, and mesothelioma [20, 22, 31, 32]. Interestingly, while RITA triggered CDKN1A and MDM2 transcription in the HD-MB03 cell line, which harbors wildtype TP53 , in vitro , only MDM2 transcription was increased in xenograft tumors derived from HD-MB03 cells in mice receiving 3 days of the more intensive treatment in our study.…”

Section: Discussionsupporting

confidence: 93%

RITA displays anti-tumor activity in medulloblastomas independent of TP53 status

et al. 2017

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Current therapy of medulloblastoma, the most common malignant brain tumor of childhood, achieves 40–70% survival. Secondary chemotherapy resistance contributes to treatment failure, where TP53 pathway dysfunction plays a key role. MDM2 interaction with TP53 leads to its degradation. Reactivating TP53 functionality using small-molecule inhibitors, such as RITA, to disrupt TP53-MDM2 binding may have therapeutic potential. We show here that RITA decreased viability of all 4 analyzed medulloblastoma cell lines, regardless of TP53 functional status. The decrease in cell viability was accompanied in 3 of the 4 medulloblastoma cell lines by accumulation of TP53 protein in the cells and increased CDKN1A expression. RITA treatment in mouse models inhibited medulloblastoma xenograft tumor growth. These data demonstrate that RITA treatment reduces medulloblastoma cell viability in both in vitro and in vivo models, and acts independently of cellular TP53 status, identifying RITA as a potential therapeutic agent to treat medulloblastoma.

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Section: Discussionsupporting

confidence: 93%

RITA displays anti-tumor activity in medulloblastomas independent of TP53 status

et al. 2017

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“…We found in wild-typep53–expressing CRC cells HCT116, HROC113, and LS174T both accumulation of p53 and elevated transcriptional levels of p53 targets p21 and NOXA . Di Marzo et al presented data that RITA also reactivates function of mutated p53 in malignant mesothelioma [28]. This is in line with results of our study as we identified three CRC cell lines (HROC183, HT29, and SW480) harboring mutant p53 with pronounced sensitivity to RITA.…”

Section: Discussionsupporting

confidence: 92%

Reactivating p53 and Inducing Tumor Apoptosis (RITA) Enhances the Response of RITA-Sensitive Colorectal Cancer Cells to Chemotherapeutic Agents 5-Fluorouracil and Oxaliplatin

et al. 2017

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Colorectal carcinoma (CRC) is the most common cancer of the gastrointestinal tract with frequently dysregulated intracellular signaling pathways, including p53 signaling. The mainstay of chemotherapy treatment of CRC is 5-fluorouracil (5FU) and oxaliplatin. The two anticancer drugs mediate their therapeutic effect via DNA damage-triggered signaling. The small molecule reactivating p53 and inducing tumor apoptosis (RITA) is described as an activator of wild-type and reactivator of mutant p53 function, resulting in elevated levels of p53 protein, cell growth arrest, and cell death. Additionally, it has been shown that RITA can induce DNA damage signaling. It is expected that the therapeutic benefits of 5FU and oxaliplatin can be increased by enhancing DNA damage signaling pathways. Therefore, we highlighted the antiproliferative response of RITA alone and in combination with 5FU or oxaliplatin in human CRC cells. A panel of long-term established CRC cell lines (n = 9) including p53 wild-type, p53 mutant, and p53 null and primary patient-derived, low-passage cell lines (n = 5) with different p53 protein status were used for this study. A substantial number of CRC cells with pronounced sensitivity to RITA (IC50< 3.0 μmol/l) were identified within established (4/9) and primary patient-derived (2/5) CRC cell lines harboring wild-type or mutant p53 protein. Sensitivity to RITA appeared independent of p53 status and was associated with an increase in antiproliferative response to 5FU and oxaliplatin, a transcriptional increase of p53 targets p21 and NOXA, and a decrease in MYC mRNA. The effect of RITA as an inducer of DNA damage was shown by a strong elevation of phosphorylated histone variant H2A.X, which was restricted to RITA-sensitive cells. Our data underline the primary effect of RITA, inducing DNA damage, and demonstrate the differential antiproliferative effect of RITA to CRC cells independent of p53 protein status. We found a substantial number of RITA-sensitive CRC cells within both panels of established CRC cell lines and primary patient-derived CRC cell lines (6/14) that provide a rationale for combining RITA with 5FU or oxaliplatin to enhance the antiproliferative response to both chemotherapeutic agents.

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“…This treatment was effective both in p53 wild-type cell lines, namely IST-MES1 (Sanger Institute, Catalogue of Somatic Mutations in Cancer) and MSTO-211H, 27 and p53 mutated cell lines, namely NCI-H2452, 27 REN, 28 and IST-MES2. 29 However, in all the p53 wild-type cell lines examined in this study (IST-MES1, NCI-H2052, 27 and MSTO-211H) the gene encoding p14, a positive p53 regulator able to inhibit the MDM2-dependent degradation of p53, 30 was previously found to be mutated (Sanger Institute, Catalogue of Somatic Mutations in Cancer). Therefore, p53 might be functionally inactive in these p53 wild-type cells lines.…”

Section: Discussionmentioning

confidence: 81%

Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma

Indovina

Marcelli

Marzo

et al. 2014

Cancer Biology & Therapy

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Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma

Cited by 34 publications

References 54 publications

RITA displays anti-tumor activity in medulloblastomas independent of TP53 status

RITA displays anti-tumor activity in medulloblastomas independent of TP53 status

Reactivating p53 and Inducing Tumor Apoptosis (RITA) Enhances the Response of RITA-Sensitive Colorectal Cancer Cells to Chemotherapeutic Agents 5-Fluorouracil and Oxaliplatin

Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma

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Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma

Cited by 34 publications

References 54 publications

RITA displays anti-tumor activity in medulloblastomas independent of TP53 status

RITA displays anti-tumor activity in medulloblastomas independent of TP53 status

Reactivating p53 and Inducing Tumor Apoptosis (RITA) Enhances the Response of RITA-Sensitive Colorectal Cancer Cells to Chemotherapeutic Agents 5-Fluorouracil and Oxaliplatin

Abrogating G2/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma

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Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma