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Molecular trail for the anticancer behavior of a novel copper carbohydrazone complex in BRCA1 mutated breast cancer

Rakesh Sathish Nair1, Manoj Easwaran Potti2, Ratheeshkumar Thankappan1

  • 1Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud, Thiruvananthapuram, Kerala, India.

Molecular Carcinogenesis
|January 5, 2017
PubMed

Insights

Novel copper complexes show potent anticancer activity against breast cancer cells. The compound CS2, combined with Pb, demonstrates synergistic effects by inducing DNA damage and apoptosis, particularly in BRCA1-mutated cells.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Metal-Organic Chemistry

Background:

  • Breast cancer exhibits diverse subtypes, including those with BRCA1 mutations, necessitating novel therapeutic strategies.
  • Metal-based drugs offer unique mechanisms of action for cancer treatment.
  • Carbohydrazone and thiocarbohydrazone ligands can form metal complexes with potential biological activity.

Purpose of the Study:

  • To synthesize novel metal-chelated complexes from carbohydrazones and thiocarbohydrazones.
  • To evaluate the anticancer activity of these complexes, particularly copper complexes, against a panel of breast cancer cell lines with varying BRCA1 and ER statuses.
  • To investigate the synergistic effects of a potent copper complex (CS2) in combination with Pb (a naphthoquinone) in breast cancer cells.

Main Methods:

  • Synthesis of novel metal complexes using metal-based drug design principles.
  • Screening of synthesized complexes for in vitro anticancer activity against a panel of breast cancer cell lines (MCF-7, MDA-MB-231, HCC-1937, MX1, MDA-MB-436).
  • Investigation of the mechanism of action, including DNA binding, DNA damage induction (γ-H2AX), Topoisomerase II inhibition, and apoptosis induction.
  • Evaluation of combination therapy effects with Pb in HR/BRCA1 defective breast cancer cells.

Main Results:

  • The copper complex Cu₂(HL)(HSO₄)·H₂O]SO₄·6H₂O (CS2) emerged as the most potent anticancer agent among the synthesized copper complexes.
  • CS2 demonstrated significant cytotoxicity, potentially enhanced by the sulfate counterion.
  • CS2 was found to bind to DNA, inhibit BamH1 activity, induce DNA double-strand breaks (evidenced by γ-H2AX), and act as a Topoisomerase II inhibitor at low concentrations.
  • CS2 induced apoptosis and exhibited synergistic anticancer activity when combined with Pb in HR/BRCA1 defective breast cancer cells.

Conclusions:

  • CS2 is a highly potent anticancer agent with a promising mechanism of action involving DNA damage and apoptosis induction.
  • The sulfate moiety in CS2 may contribute to its enhanced cytotoxicity.
  • The combination of CS2 and Pb shows significant synergistic anticancer effects in BRCA1-mutated breast cancer cells, highlighting a potential new therapeutic approach for this subtype.
Keywords:
DNA damageanticancer activitycopper carbohydrazone complexplumbagin

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