Abstract
In this work we explored the possibility of using genetically modified Arabidopsis thaliana plants as a rapid and low-cost screening tool for evaluating human anticancer drugs action and efficacy. Here, four different inhibitors with a validated anticancer effect in humans and distinct mechanism of action were screened in the plant model for their ability to interfere with the cytoskeletal and endomembrane networks. We used plants expressing a green fluorescent protein (GFP) tagged microtubule-protein (TUA6-GFP), and three soluble GFPs differently sorted to reside in the endoplasmic reticulum (GFPKDEL) or to accumulate in the vacuole through a COPII dependent (AleuGFP) or independent (GFPChi) mechanism. Our results demonstrated that drugs tested alone or in combination differentially influenced the monitored cellular processes including cytoskeletal organization and endomembrane trafficking. In conclusion, we demonstrated that A. thaliana plants are sensitive to the action of human chemotherapeutics and can be used for preliminary screening of drugs efficacy. The cost-effective subcellular imaging in plant cell may contribute to better clarify drugs subcellular targets and their anticancer effects.
Highlights
The search for more effective human therapies is one of the most important objectives of modern chemistry and biology
The action of four different drug inhibitors was investigated in the model plant A. thaliana
Tagged microtubule-protein TUA6 (GFP-TUA6, Figure 1A.1,A.2) [22], the endomembrane system was labeled by three soluble green fluorescent protein (GFP) differently sorted to reside in the endoplasmic reticulum (ER) (GFPKDEL; Figure 1A.3) [23], to accumulate in the vacuole through a COPII dependent transport mechanism (AleuGFP; Figure 1A.4,A.5) or through a COPII independent mechanism (GFPChi; Figure 1A.6)
Summary
The search for more effective human therapies is one of the most important objectives of modern chemistry and biology. The development of a new drug has become increasingly dependent on an understanding of tumor biology and the path to success for targeted-molecules, strongly correlated to the comprehension of their biological mechanism of action including possible side effects. A limiting factor is the cost of screening studies to identify the subcellular and molecular targets of new compounds. Besides the active inhibition of a specific ligand, several chemotherapeutics can potentiate their cytotoxic effects through the modulation or other pathways and the interplay with several cellular specialization [3]. This can have several implications for patient outcome including drug-side effects
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