Cisplatin, Oxaliplatin, and Kiteplatin Subcellular Effects Compared in a Plant Model.

Paride Papadia,Gian-Pietro Di Sansebastiano,Gabriella Piro,Fabrizio Barozzi,Nicola Margiotta,James Hoeschele

doi:10.3390/ijms18020306

Abstract

The immediate visual comparison of platinum chemotherapeutics’ effects in eukaryotic cells using accessible plant models of transgenic Arabidopsis thaliana is reported. The leading anticancer drug cisplatin, a third generation drug used for colon cancer, oxaliplatin and kiteplatin, promising Pt-based anticancer drugs effective against resistant lines, were administered to transgenic A. thaliana plants monitoring their effects on cells from different tissues. The transgenic plants’ cell cytoskeletons were labelled by the green fluorescent protein (GFP)-tagged microtubule-protein TUA6 (TUA6-GFP), while the vacuolar organization was evidenced by two soluble chimerical GFPs (GFPChi and AleuGFP) and one transmembrane GFP-tagged tonoplast intrinsic protein 1-1 (TIP1.1-GFP). The three drugs showed easily recognizable effects on plant subcellular organization, thereby providing evidence for a differentiated drug targeting. Genetically modified A. thaliana are confirmed as a possible rapid and low-cost screening tool for better understanding the mechanism of action of human anticancer drugs.

Highlights

Platinum drugs (cisplatin, cis-diamminedichloridoplatinum(II), CDDP; carboplatin, diammine [1,1-cyclobutanedicarboxylato] platinum(II); and oxaliplatin, [(1R,2R)-cyclohexane-1,2-diamine]platinum(II)) are widely used in the clinic and the prototype cisplatin has proven to be effective in the treatment of a variety of tumors such as testicular, ovarian, bladder, head and neck, and small and non-small cell lung cancers [1,2,3,4,5,6,7]
We propose the use of transgenic plants expressing green fluorescent protein (GFP)-tagged markers as a low-cost platform for the visualization of the effects generated cisplatin-related compounds and subcellular targets in order to evidence differential biological effects in rapid in vivo preliminary screenings
We propose the use of transgenic plants expressing GFP-tagged markers as a low-cost platform for the visualization of the effects generated by three Pt anticancer compounds, two already in clinical use, cisplatin and oxaliplatin, and one oxaliplatin analog currently under study, kiteplatin [14,15,16,17,35]

Summary

Introduction

Platinum drugs (cisplatin, cis-diamminedichloridoplatinum(II), CDDP; carboplatin, diammine [1,1-cyclobutanedicarboxylato] platinum(II); and oxaliplatin, [(1R,2R)-cyclohexane-1,2-diamine] (ethanedioato)platinum(II)) are widely used in the clinic and the prototype cisplatin has proven to be effective in the treatment of a variety of tumors such as testicular, ovarian, bladder, head and neck, and small and non-small cell lung cancers [1,2,3,4,5,6,7]. Oxaliplatin, in particular, contains the 1R,2R-DACH (DACH, diaminocyclohexane) carrier ligand and currently is one of the most important therapeutic agents used as an adjuvant in the treatment of stage III colon cancer (as part of the FOLFOX, FOLFOXFIRI, and CapeOX chemotherapeutic regimens). The compound PtCl2(cis-1,4-DACH), dubbed kiteplatin (Figure 1), contains an isomeric form of the oxaliplatin diamine ligand and was introduced into Pt-based drug research many years ago as an alternative to 1R,2R-DACH Pt-compounds [12]. Notwithstanding some initial interest due to the fact that kiteplatin exhibited better in vitro cytotoxicity than cisplatin and substantial in vivo

Methods

Results

Conclusion