Abstract
5-Azactydine inhibits cell growth by direct cytotoxic action as well as by inhibition of DNA methyl transferase enzyme. Inhibitors of DNMT have been reported to potentiate the therapeutic activity of cisplatin in vitro. Dose dependent bone marrow toxicity, neurotoxicity and nephrotoxicity are the major side effects of cisplatin, limiting its use as an effective chemotherapeutic agent. The present study was aimed to reduce the nephrotoxic potential of cisplatin without compensating its potency. To best of our knowledge, this is the first report which shows that the combination of 5-azacytidine with cisplatin leads to remarkable reduction in nephrotoxicity, by involving inhibition of cisplatin induced metallothionein expression. 5-Azacytidine treatment with cisplatin leads to maximum reduction in tumor size in DMH induced colon cancer and tumor volume in DMBA induced breast cancer bearing SD rats. This combination regimen prevents phosphorylation and acetylation of histone H3 which may be involved in inhibition of aberrant gene expression in colon tumors. Further, 5-azacytidine potentiated cisplatin induced antitumor activity by involving decreased expression of pAKT, DNMT1 and an increased expression of p38 in colon tumors. Thus, combination of 5-azactydine with cisplatin attenuates the cisplatin induced nephrotoxicity and potentiates the anti-cancer activity which can have profound clinical implications.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimetabolites, Antineoplastic / pharmacology*
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / toxicity*
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Azacitidine / pharmacology*
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Blood Urea Nitrogen
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Blotting, Western
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Breast Neoplasms / drug therapy
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Breast Neoplasms / pathology
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Breast Neoplasms / prevention & control
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Cell Nucleus / immunology
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Cisplatin / antagonists & inhibitors*
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Cisplatin / pharmacology
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Cisplatin / toxicity*
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Colonic Neoplasms / drug therapy
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Creatinine / blood
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / biosynthesis*
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / physiology
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Drug Synergism
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Drug Therapy, Combination
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Female
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Histones / metabolism
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Kidney Diseases / chemically induced*
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Kidney Diseases / prevention & control*
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Male
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / pathology
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Mammary Neoplasms, Experimental / prevention & control
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Metallothionein / biosynthesis*
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Metallothionein / genetics
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Metallothionein / physiology
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Neoplasms, Experimental / chemically induced*
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Neoplasms, Experimental / prevention & control*
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Proliferating Cell Nuclear Antigen / biosynthesis
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Proto-Oncogene Proteins c-akt / biosynthesis*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / physiology
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Rats
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Rats, Sprague-Dawley
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p38 Mitogen-Activated Protein Kinases / biosynthesis
Substances
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Antimetabolites, Antineoplastic
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Antineoplastic Agents
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Histones
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Proliferating Cell Nuclear Antigen
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Metallothionein
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Creatinine
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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Dnmt1 protein, rat
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Proto-Oncogene Proteins c-akt
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p38 Mitogen-Activated Protein Kinases
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Azacitidine
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Cisplatin