Cytotoxic efficacy of an anthraquinone linked platinum anticancer drug

R. A. Alderden, H. R. Mellor, S. Modok, T. W. Hambley, R. Callaghan

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Platinum complexes are widely used in cancer chemotherapy; however, they are associated with toxicity, high "non-specific" reactivity and relatively poor pharmacokinetic profiles. In particular, their low cellular uptake and rapid metabolic inactivation means that the amount of "active" drug reaching the nuclear compartment is low. Our strategy to facilitate nuclear accumulation was to introduce a hydrophobic anthraquinone (1C3) moiety to the Pt-complex. Anthraquinones are known to readily intercalate into DNA strands and hence, the Pt-1C3 complex may represent an effective system for the delivery of the platinum moiety to nuclear DNA. Efficacy of the complex was determined by measuring the extent and potency of cytotoxicity in comparison to cisplatin and an anthraquinone based anticancer drug, doxorubicin. The Pt-1C3 complex generated higher levels of cytotoxicity than cisplatin, with a potency of 19 ± 4 μM in the DLD-1 cancer cell line. However, this potency was not significantly different to that of the 1C3 moiety alone. To examine the reason for the apparent lack of platinum related cytotoxicity, the cellular distribution was characterised. Confocal fluorescence microscopy indicated that the Pt-1C3 complex was rapidly sequestered into lysosomes, in contrast to the nuclear localisation of doxorubicin. In addition, there was negligible DNA associated Pt following administration of the novel complex. Thus, the addition of a 1C3 moiety generated sequestration of the complex to lysosomes, thereby preventing localisation to the nucleus.

Original languageEnglish
Pages (from-to)1136-1145
Number of pages10
JournalBiochemical Pharmacology
Volume71
Issue number8
DOIs
Publication statusPublished - Apr 14 2006

Fingerprint

Anthraquinones
Cytotoxicity
Platinum
Lysosomes
Doxorubicin
Cisplatin
DNA
Pharmaceutical Preparations
Pharmacokinetics
Chemotherapy
Confocal microscopy
Fluorescence microscopy
Fluorescence Microscopy
Confocal Microscopy
Toxicity
Neoplasms
Cells
Drug Therapy
Cell Line

Keywords

  • Anthraquinone
  • Cancer
  • Chemotherapy
  • Cytotoxicity
  • Lysosomes
  • Platinum

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cytotoxic efficacy of an anthraquinone linked platinum anticancer drug. / Alderden, R. A.; Mellor, H. R.; Modok, S.; Hambley, T. W.; Callaghan, R.

In: Biochemical Pharmacology, Vol. 71, No. 8, 14.04.2006, p. 1136-1145.

Research output: Contribution to journalArticle

Alderden, R. A. ; Mellor, H. R. ; Modok, S. ; Hambley, T. W. ; Callaghan, R. / Cytotoxic efficacy of an anthraquinone linked platinum anticancer drug. In: Biochemical Pharmacology. 2006 ; Vol. 71, No. 8. pp. 1136-1145.
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