New in vitro highly cytotoxic platinum and palladium cyanoximates with minimal side effects in vivo

Stephanie D. Dannen, Lauren Cornelison, Paul Durham, John E. Morley, Kiana Shahverdi, Junwei Du, Haiying Zhou, Leland C. Sudlow, Daniel Hunter, Matthew D. Wood, Mikhail Y. Berezin, Nikolay Gerasimchuk

Research output: Contribution to journalArticle

Abstract

Several biologically active bivalent Pd and Pt complexes with two structurally similar cyanoxime ligands abbreviated as H(DECO): 2-oximino-2-cyano-N,N′-diethylacetamide, and H(PyrCO): 2-oximino-2-cyan-N-pyrrolidine acetamide were synthesized and characterized using spectroscopic methods, thermal analysis and X-ray crystallography. Structures revealed planar cis-geometry of studied complexes. Freshly obtained Pt(DECO)2, Pd(DECO)2, Pt(PyrCO)2 and Pd(PyrCO)2 complexes were used in for in vitro cytotoxicity assays using two different etiology human cancer cell lines HeLa and WiDr cells. Investigated compounds showed cytotoxicity levels at or above cisplatin. Pt(DECO)2 was also tested in vivo in healthy C57BL/6 mice. The complex was administered at three different dosage (0, 7.5, 15 mg/kg, i.p. once/week), over a total period of 8 weeks. No changes were observed in the animal weight in the treated mice compared to the control dextrose-treated group. The levels of erythrocytes, leukocytes, and hemoglobin were within the normal level suggesting low myelotoxicity. Negligible cardiotoxicity was observed from the histological evaluation of the hearts from the treated animals. Results from the tail nerve conduction velocity (NCV) and nerve histomorphometry suggested no impact of Pt(DECO)2 on peripheral nerves. The complex, however, induced certain hepatotoxicity and lead to the elevation of IL-6, a pro-inflammatory cytokine. Overall, Pt(DECO)2 showed minimal in vivo toxicity, thus presenting a promising candidate for future testing in animal models of cancer.

Original languageEnglish
Article number111082
JournalJournal of Inorganic Biochemistry
Volume208
DOIs
StatePublished - Jul 2020

Keywords

  • Animal model
  • Crystal structures
  • Human cancer cells
  • Pd/Pt-cyanoximates
  • in vitro studies
  • in vivo studies

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    Dannen, S. D., Cornelison, L., Durham, P., Morley, J. E., Shahverdi, K., Du, J., Zhou, H., Sudlow, L. C., Hunter, D., Wood, M. D., Berezin, M. Y., & Gerasimchuk, N. (2020). New in vitro highly cytotoxic platinum and palladium cyanoximates with minimal side effects in vivo. Journal of Inorganic Biochemistry, 208, [111082]. https://doi.org/10.1016/j.jinorgbio.2020.111082