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Combinatorial Therapy of Zinc Metallochaperones with Mutant p53 Reactivation and Diminished Copper Binding.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2019 Aug; Vol. 18 (8), pp. 1355-1365. Date of Electronic Publication: 2019 Jun 13. - Publication Year :
- 2019
-
Abstract
- Chemotherapy and radiation are more effective in wild-type (WT) p53 tumors due to p53 activation. This is one rationale for developing drugs that reactivate mutant p53 to synergize with chemotherapy and radiation. Zinc metallochaperones (ZMC) are a new class of mutant p53 reactivators that restore WT structure and function to zinc-deficient p53 mutants. We hypothesized that the thiosemicarbazone, ZMC1, would synergize with chemotherapy and radiation. Surprisingly, this was not found. We explored the mechanism of this and found the reactive oxygen species (ROS) activity of ZMC1 negates the signal on p53 that is generated with chemotherapy and radiation. We hypothesized that a zinc scaffold generating less ROS would synergize with chemotherapy and radiation. The ROS effect of ZMC1 is generated by its chelation of redox active copper. ZMC1 copper binding ( K <subscript>Cu</subscript> ) studies reveal its affinity for copper is approximately 10 <superscript>8</superscript> greater than Zn <superscript>2+</superscript> We identified an alternative zinc scaffold (nitrilotriacetic acid) and synthesized derivatives to improve cell permeability. These compounds bind zinc in the same range as ZMC1 but bound copper much less avidly (10 <superscript>6</superscript> - to 10 <superscript>7</superscript> -fold lower) and induced less ROS. These compounds were synergistic with chemotherapy and radiation by inducing p53 signaling events on mutant p53. We explored other combinations with ZMC1 based on its mechanism of action and demonstrate that ZMC1 is synergistic with MDM2 antagonists, BCL2 antagonists, and molecules that deplete cellular reducing agents. We have identified an optimal Cu <superscript>2+</superscript> :Zn <superscript>2+</superscript> binding ratio to facilitate development of ZMCs as chemotherapy and radiation sensitizers. Although ZMC1 is not synergistic with chemotherapy and radiation, it is synergistic with a number of other targeted agents.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Cell Line
Combined Modality Therapy
Humans
Metallochaperones genetics
Mice
Protein Binding
Pyridines pharmacology
Radiation
Reactive Oxygen Species metabolism
Signal Transduction drug effects
Signal Transduction radiation effects
Copper metabolism
Metallochaperones metabolism
Mutation
Transcriptional Activation drug effects
Transcriptional Activation radiation effects
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Zinc metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 18
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 31196889
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-18-1080