Ternary copper(II) complex: NCI60 screening, toxicity studies, and evaluation of efficacy in xenograft models of nasopharyngeal carcinoma

PLoS One. 2018 Jan 12;13(1):e0191295. doi: 10.1371/journal.pone.0191295. eCollection 2018.

Abstract

Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4. The complex significantly inhibited tumor growth in nasopharyngeal carcinoma xenograft bearing mice models at doses which were well tolerated without causing significant or permanent toxic side effects. However, higher doses which resulted in better inhibition of tumor growth also resulted in toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Carcinoma / drug therapy*
  • Carcinoma / pathology
  • Cell Line, Tumor
  • Copper / chemistry*
  • Cytochrome P-450 Enzyme Inhibitors / chemistry
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • Cytochrome P-450 Enzyme Inhibitors / toxicity
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Female
  • Hepatocytes / drug effects
  • Mice
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Neoplasms / drug therapy*
  • Nasopharyngeal Neoplasms / pathology
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / pharmacology*
  • Organometallic Compounds / toxicity
  • Rats
  • Xenograft Model Antitumor Assays*

Substances

  • Antineoplastic Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Organometallic Compounds
  • Copper
  • Cytochrome P-450 Enzyme System

Grants and funding

This work was supported by Ministry of Health Malaysia (JPP 12-046; NMRR-13-898-17054) and Ministry of Science, Technology and Innovation eScience grants (02-02-SF0033; 02-02-09-SF0036). The funders did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Aurigene Discovery Technologies Limited provided support in the form of salaries for author [DSS], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The salaries of authors [MA, SNS, TLC, NAA, NKMK, KWL, CHN, ASBK] were through their respective institutes independent of the grants. The specific roles of these authors are articulated in the 'author contributions' section.