p53‐Based strategy to reduce hematological toxicity of chemotherapy: A proof of principle study

Ha, Chul S.; Michalek, Joel E.; Elledge, Richard M.; Kelly, Kevin R.; Ganapathy, Suthakar; Su, Hang; Jenkins, Carol; Argiris, Athanassios; Swords, Ronan; Eng, Tony Y.; Karnad, Anand B.; Crownover, Richard L.; Swanson, Gregory P.; Goros, Martin; Pollock, Brad H.; Yuan, Zhi Min

doi:10.1016/j.molonc.2015.09.004

Cited by 10 publications

(8 citation statements)

References 27 publications

(41 reference statements)

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“…This study provides a proof of concept that a C646-like p53 inhibitor may improve the clinical outcome of patients undergoing chemotherapy, especially for those with p53-mutant tumors. In a recent clinical study, patients who received a low dose of arsenic trioxide, which transiently blocked p53 activation, showed resistance to myelosuppression after four or more cycles of chemotherapy (42).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

et al. 2017

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Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a firstline chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed.Cancer Res; 77(16); 4342-54. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 99%

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

et al. 2017

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“…Taken together with our recent work (10), these results provide further support for utilizing inhibitors of p53 during radiation exposure to not only ameliorate acute radiation injury, but also to prevent radiation-induced tumorigenesis. Notably, using low-dose arsenic to inhibit p53 during administration of chemotherapy was recently shown to reduce hematologic toxicity in a clinical trial (33). Although the increase in lung tumor size following radiation in super p53 mice was relatively small, our findings raise the possibility that drugs that increase p53 signaling during radiation exposure, such as Mdm2 inhibitors, could promote cancer progression.…”

Section: Discussionmentioning

confidence: 99%

An extra copy of p53 suppresses development of spontaneous Kras-driven but not radiation-induced cancer

Moding¹,

Min²,

Castle³

et al. 2016

JCI Insight

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The tumor suppressor p53 blocks tumor progression in multiple tumor types. Radiation-induced cancer following exposure to radiation therapy or space travel may also be regulated by p53 because p53 has been proposed to respond to DNA damage to suppress tumorigenesis. Here, we investigate the role of p53 in lung carcinogenesis and lymphomagenesis in LA-1 KrasG12D mice with wild-type p53 or an extra copy of p53 (super p53) exposed to fractionated total body irradiation with low linear energy transfer (low-LET) X-rays or high-LET iron ions and compared tumor formation in these mice with unirradiated controls. We found that an additional copy of p53 suppressed both Kras-driven lung tumor and lymphoma development in the absence of radiation. However, an additional copy of p53 did not affect lymphoma development following low- or high-LET radiation exposure and was unable to suppress radiation-induced expansion of thymocytes with mutated Kras. Moreover, radiation exposure increased lung tumor size in super p53 but not wild-type p53 mice. These results demonstrate that although p53 suppresses the development of spontaneous tumors expressing KrasG12D, in the context of exposure to ionizing radiation, an extra copy of p53 does not protect against radiation-induced lymphoma and may promote KrasG12D mutant lung cancer.

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“…This approach has recently shown hematopoietic protection in humans receiving myelosuppressive chemotherapy in a recently reported clinical trial (260). …”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

Carr¹,

Jones²

2016

Transl. Cancer Res.

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The p53 tumor suppressor acts as a guardian of the genome in mammalian cells undergoing DNA double strand breaks induced by a various forms of cell stress, including inappropriate growth signals or ionizing radiation. Following damage, p53 protein levels become greatly elevated in cells and p53 functions primarily as a transcription factor to regulate the expression a wide variety of genes that coordinate this DNA damage response. In cells undergoing high amounts of DNA damage, p53 can promote apoptosis, whereas in cells undergoing less damage, p53 promotes senescence or transient cell growth arrest and the expression of genes involved in DNA repair, depending upon the cell type and level of damage. Failure of the damaged cell to undergo growth arrest or apoptosis, or to respond to the DNA damage by other p53-coordinated mechanisms, can lead to inappropriate cell growth and tumorigenesis. In cells that have successfully responded to genetic damage, the amount of p53 present in the cell must return to basal levels in order for the cell to resume normal growth and function. Although regulation of p53 levels and function is coordinated by many proteins, it is now widely accepted that the master regulator of p53 is Mdm2. In this review, we discuss the role(s) of p53 in the DNA damage response and in tumor suppression, and how post-translational modification of Mdm2 regulates the Mdm2-p53 signaling axis to govern p53 activities in the cell.

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p53‐Based strategy to reduce hematological toxicity of chemotherapy: A proof of principle study

Cited by 10 publications

References 27 publications

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

An extra copy of p53 suppresses development of spontaneous Kras-driven but not radiation-induced cancer

Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

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