Publication: Novel organo-osmium(II) proteosynthesis inhibitors active against human ovarian cancer cells reduce gonad tumor growth in Caenorhabditis elegans
Authors
Ortega, Enrique ; Ballester, Francisco J. ; Hernández García, Alba ; Hernández García, Samanta ; Guerrero Rubio, M. Alejandra ; Bautista, Delia ; Santana, M. Dolores ; Ruiz, José ; Gandía Herrero, Fernando
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SAI, Universidad de Murcia,
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Publisher
Royal Society of Chemistry
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DOI
https://doi.org/10.1039/C9QI01704F
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info:eu-repo/semantics/article
Description
© the Partner Organisations 2021. This document is the Published version of a Published Work that appeared in final form in Inorganic Chemistry Frontiers. To access the final edited and published work see DOI https://doi.org/10.1039/C9QI01704F
Abstract
This work reports the synthesis and characterization of some novel osmium(II) complexes with potential
as anticancer drugs tested in vitro and in vivo. The complexes have a structure [(η6
-p-cym)Os(C^N)(X)]0/+,
where the C^N ligand is deprotonated 2-phenylpyridine (ppy) or 4-(2-pyridin)benzaldehyde (ppy-CHO)
and X is chloride, pyridine (py) or the pyridine derivative 4-NMe2-py. The in vitro cytotoxic studies
showed that complexes [(η6
-p-cym)Os(C^N)(4-NMe2-py)]+ (C^N = ppy 2a and ppy-CHO 5a) exerted
effective antiproliferative activity towards both cisplatin-sensitive ovarian cancer cells (A2780) and cisplatin-resistant cells (A2780cis). The mechanism underlying the antiproliferative effects in vitro was studied
showing a reduction of proteosynthesis up to 58% and an increase of apoptosis modulated by caspase-3.
Model animal Caenorhabditis elegans was used to estimate the effects of 2a and 5a and the in-house
4-NMe2-py Ru(II) analogue 5b in vivo. Compounds 2a, 5a and 5b were able to reduce tumor growth up
32.2%, 19% and 30%, respectively in the tumoral strain JK1466 and presented low toxicity in both tumoral
and wild-type strains. The mechanistic study using reporter gene expression showed that 2a, 5a and 5b
were able to maintain the reactive oxygen species (ROS) levels in the animals by increased expression of
the mitochondrial superoxide dismutase 3 (SOD-3), an indication that they were able to regulate oxidative
stress genes specifically. Interestingly the three complexes showed a similar mechanism of action,
suggesting that the identity of the metal ion does not matter and the effect is more related to the whole
structure of the complex. Worthy of note, cisplatin treatment produced elevated ROS levels in the animals
and induced the expression of glutathione transferase 4 (GST-4) suggesting different mechanisms of
action for the two complexes. Altogether the results showed that osmium(II) complexes can be potential
candidates in the search for novel chemotherapeutic drugs.
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Citation
Inorganic Chemistry Frontiers, 2021, Vol. 8, pp. 141-155
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