The effect of cisplatin and platinum(IV)chloride on cell growth, RNA, protein, ribosome and DNA synthesis in yeast

Abstract

The effect of cisplatin and platinum(IV)chloride on growth, RNA, ribosome, and DNA synthesis were tested in growing yeast cells. Treatment with both compounds causes comparable reduction but not a significant delay in the course of growth and RNA synthesis as well as DNA, and ribosome synthesis rates. The results were evaluated on the basis of a test system for rapid differentiation of nuclear and cytoplasmatic damage, which is founded on qualitative changes in growth curves and in synthesis rates. These observations indicate that PtCl 4 as well as cisplatin cause defects in the nuclear DNA. A quantitative comparison suggests that there exist differences in the nature of the DNA damage.

RNA-Pt Adducts Following Cisplatin Treatment of Saccharomyces cerevisiae

“…In yeast, global protein synthesis is dramatically reduced as early as 2–4 hr post-cisplatin treatment, indicating a compromised translation machine, which may be a result of mRNA, tRNA, or rRNA modifications (27). In general, cationic aquated Pt species are expected to associate more readily with accessible sites in higher-order RNA structures, which present a larger electrostatic driving force (50).…”

“…26 For cultured cells, however, significant cisplatin aquation may take place in the media. In rich media such as YEPD (yeast extract peptone dextrose), the highly reactive aquation products may interact with soft sulfur-and nitrogen-containing nucleophiles to effectively sequester the drug, which could be one reason for IC 50 measurements higher than those observed in mammalian and cancer cell lines (e.g., 500 μM in S. cerevisiae in YEPD media (27) versus 2−40 μM for human cancer cell lines 28−30 ). We therefore assayed drug toxicity in minimal SD (synthetic dextrose) liquid media (Figure 1a) and found a moderate (76 ± 8%) and severe (36 ± 1%) reduction in culture density at saturation for 100 and 200 μM drug, respectively.…”

“…In yeast, global protein synthesis is dramatically reduced as early as 2−4 h post-cisplatin treatment, indicating a compromised translation machine, which may be a result of mRNA, tRNA, or rRNA modifications. 27 In general, cationic aquated Pt species are expected to associate more readily with accessible sites in higher-order RNA structures, which present a larger electrostatic driving force. 50 The enrichment of Pt on rRNA relative to poly(A)-mRNA (Figure 4c) may be due to the high negative charge density of the ribosome and may present a contributing factor to cisplatin's cytotoxicity.…”