The cisplatin analogues cis-[PtCl2(3ClHaza)2] (1) and cis-[PtCl2(3IHaza)2] (2) (3ClHaza and 3IHaza are 3-chloro-7-azaindole and 3-iodo-7-azaindole, respectively) are quite toxic to ovarian tumor cells, with moderately better IC50 values than for cisplatin in the cisplatin-sensitive cell line A2780. We investigated potential factors which might be involved in the mechanism underlying the cytotoxic effects of 1 and 2 and compared these factors with those involved in the mechanism underlying the effects of conventional cisplatin. Our data indicate that the higher cytotoxicity of 1 and 2 originates mainly from their efficient cellular accumulation, different effects at the level of cell cycle regulation, and reduced propensity for DNA adduct repair. Studies of their reactivity toward cellular components reveal efficient binding to DNA, which is typically required for an active platinum drug. Further results suggest that 1 and 2 are capable of circumventing resistance to cisplatin induced by alterations in cellular accumulation and DNA repair. Hence, the latter two factors appear to be responsible for differences in the toxicity of 1 or 2, and cisplatin in tumor cells. The results of this work reinforce the idea that direct analogues of conventional cisplatin-containing halogeno-substituted 7-azaindoles offer much promise for the design of novel therapeutic agents.

Department of Biophysics Faculty of Sciences Palacky University 17 listopadu 12 77146 Olomouc Czech Republic

Zobrazit více v PubMed

Biochemistry. 1990 Jan 30;29(4):1016-24 PubMed

Curr Med Chem. 2003 Feb;10(3):257-66 PubMed

Biochemistry. 1990 Oct 16;29(41):9522-31 PubMed

Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5345-9 PubMed

Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3611-6 PubMed

J Inorg Biochem. 1999 Oct;77(1-2):111-5 PubMed

Nucleic Acids Res. 1992 Jan 25;20(2):267-72 PubMed

Drugs. 2000;59 Suppl 4:1-8; discussion 37-8 PubMed

J Med Chem. 2008 Sep 11;51(17):5310-9 PubMed

Mol Pharm. 2011 Jun 6;8(3):949-57 PubMed

Nat Rev Cancer. 2007 Aug;7(8):573-84 PubMed

Cancer Res. 1994 Nov 1;54(21):5618-22 PubMed

Mol Cancer Ther. 2007 Nov;6(11):2868-78 PubMed

J Inorg Biochem. 2012 Oct;115:57-63 PubMed

Chem Res Toxicol. 2012 Feb 20;25(2):500-9 PubMed

Drug Metab Dispos. 2002 Dec;30(12):1378-84 PubMed

Oncogene. 2003 Oct 20;22(47):7265-79 PubMed

Anticancer Drug Des. 1999 Apr;14(2):143-51 PubMed

Cytometry. 2000 May 1;40(1):19-25 PubMed

Oncol Rep. 2004 Nov;12(5):955-65 PubMed

J Anal At Spectrom. 2009 Jan;24(1):51-61 PubMed

Mol Cancer. 2005 May 09;4(1):18 PubMed

Biochemistry. 1986 Jul 1;25(13):3912-5 PubMed

Drug Metab Dispos. 2003 Jul;31(7):916-23 PubMed

Cancer Chemother Pharmacol. 1996;37(5):463-71 PubMed

Cancer Res. 1999 Aug 15;59(16):3968-71 PubMed

Crit Rev Oncol Hematol. 2005 Jan;53(1):25-34 PubMed

Drug Resist Updat. 2005 Jun;8(3):131-46 PubMed

Biochemistry. 1983 Aug 2;22(16):3927-33 PubMed

Anticancer Agents Med Chem. 2007 Jan;7(1):19-34 PubMed

Mutat Res. 2001 Jul 1;478(1-2):23-43 PubMed

Chem Rev. 1999 Sep 8;99(9):2499-510 PubMed

Cell Biol Toxicol. 1995 Oct;11(5):273-81 PubMed

Nat Rev Drug Discov. 2005 Apr;4(4):307-20 PubMed

Chem Rev. 1999 Sep 8;99(9):2467-98 PubMed

Curr Med Chem Anticancer Agents. 2005 May;5(3):251-65 PubMed

Lung Cancer. 2008 Mar;59(3):377-84 PubMed

Biophysik. 1970;6(4):290-300 PubMed

Met Based Drugs. 2001;8(1):29-37 PubMed

Cancer Res. 1988 Aug 15;48(16):4484-8 PubMed

Novel cis-Pt(II) Complexes with Alkylpyrazole Ligands: Synthesis, Characterization, and Unusual Mode of Anticancer Action

In vitro anticancer active cis-Pt(II)-diiodido complexes containing 4-azaindoles

In Vitro Antitumor Active Gold(I) Triphenylphosphane Complexes Containing 7-Azaindoles

Platinum(II) Iodido Complexes of 7-Azaindoles with Significant Antiproliferative Effects: An Old Story Revisited with Unexpected Outcomes

Highly and Broad-Spectrum In Vitro Antitumor Active cis-Dichloridoplatinum(II) Complexes with 7-Azaindoles

Potentiating effect of UVA irradiation on anticancer activity of Carboplatin derivatives involving 7-azaindoles

Pharmacological and molecular effects of platinum(II) complexes involving 7-azaindole derivatives

4-aminobenzoic acid-coated maghemite nanoparticles as potential anticancer drug magnetic carriers: a case study on highly cytotoxic Cisplatin-like complexes involving 7-azaindoles