Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function

MKT-077, a cationic rhodacyanine dye analogue has been under preclinical cancer therapeutical trials because of its selective toxicity to cancer cells. Its cellular targets and mechanism of action remain poorly understood. Here we report that MKT-077 binds to an hsp70 family member, mortalin (mot-2)...

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Published inCancer research (Chicago, Ill.) Vol. 60; no. 24; pp. 6818 - 6821
Main Authors WADHWA, Renu, SUGIHARA, Takashi, YOSHIDA, Akiko, NOMURA, Hitoshi, REDDEL, Roger R, SIMPSON, Richard, MARUTA, Hiroshi, KAUL, Sunil C
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 15.12.2000
Subjects
3T3 Cells
Animals
Antineoplastic agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - toxicity
Biological and medical sciences
Chemotherapy
Chromatography, Affinity
Coloring Agents - toxicity
Cytoplasm - metabolism
Genes, Reporter
HSP70 Heat-Shock Proteins - metabolism
Humans
Medical sciences
Mice
Microscopy, Fluorescence
Mitochondrial Proteins
MKT-077
mortalin
mot-2 protein
Pharmacology. Drug treatments
Precipitin Tests
Protein Binding
Pyridines - chemistry
Pyridines - toxicity
Thiazoles - chemistry
Thiazoles - toxicity
Transcriptional Activation
Transfection
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - metabolism
Antineoplastic agent
Cationic complex
Human
Rhodamine
Dyes
Transcription
Selectivity
In vitro
Biological activity
Fixation
TP53 Gene
Analog
Established cell line
Heat shock protein
Mechanism of action
Tumor cell
Tumor suppressor gene
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Summary:MKT-077, a cationic rhodacyanine dye analogue has been under preclinical cancer therapeutical trials because of its selective toxicity to cancer cells. Its cellular targets and mechanism of action remain poorly understood. Here we report that MKT-077 binds to an hsp70 family member, mortalin (mot-2), and abrogates its interactions with the tumor suppressor protein, p53. In cancer cells, but not in normal cells, MKT-077 induced release of wild-type p53 from cytoplasmically sequestered p53-mot-2 complexes and rescued its transcriptional activation function. Thus, MKT-077 may be particularly useful for therapy of cancers with wild-type p53.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
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ISSN:0008-5472
1538-7445