In vitro interaction between Ecteinascidin 743 (ET-743) and radiation, in relation to its cell cycle effects

Abstract

Ecteinascidin 743 (ET-743) is a new marine-derived agent with promising activity against a number of solid tumours. In four human tumour cell lines, the interaction between ET-743 and radiation was investigated in relation to the effects of ET-743 on the cell cycle, in vitro. Cell survival was measured based on quantitative staining of cellular protein by sulforhodamine B. A 24 h treatment with ET-743 before radiation resulted in a moderate increase in radiosensitivity in three out of four cell lines. Dose enhancement factors X1.8 were observed for concentrations resulting in 52, 46 and 30% cell kill in ECV304, H292 and CAL-27, respectively, whereas in A549 no radiosensitisation was observed (no significant increase in radiosensitivity). According to the combination index analysis, synergism was observed only in ECV304 and CAL-27 cells. A 24 h incubation with ET-743 resulted in a concentration-dependent G2/M block, which might explain the moderate radiosensitising effects in ECV304 and H292. The lack of radiosensitisation in A549 might be due to the S phase delay preceding the G2/M block at the moment of radiation, which only occurred in this cell line. In conclusion, ET-743 has moderate cell line-dependent radiosensitising properties; however, only when cytotoxic concentrations of ET-743 are used. In one of the four cell lines tested, no radiosensitisation was observed.

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

“…Since NF-Y interacts with several essential genes involving DNA metabolism and cell-cycle regulators, 16 the inhibition of this protein can cause a delay in S-phase progression and accumulation of cells in G 2 /M phase, which is in agreement with the observation of Simoens and coworkers. 17 The inhibition of transcription factor NF-Y, however, still occurs at high concentration of Et-743, three times higher than the pharmacological concentration when pre-incubating NF-Y with Et-743.…”

Pharmacodynamic Modeling of Cell Cycle Effects for Gemcitabine and Trabectedin Combinations in Pancreatic Cancer Cells

“…The A and B subunits bind covalently to the DNA minor groove and bend DNA toward the major groove, and the C ring protrudes to interact with adjacent macromolecules such as transcription factors (D'Incalci and Galmarini, 2010). Trabectedin was found previously to cause cell cycle arrest at S and G 2 / M phases in many human tumor cell lines (Gajate et al, 2002; Simoens et al, 2003). Because of its unique mechanisms of action (D'Incalci and Galmarini, 2010), trabectedin has been reported to exert anti-tumor activities in many malignancies, including soft-tissue sarcomas, ovarian carcinomas, and breast cancer (D'Incalci et al, 2002; D'Incalci and Zambelli, 2015).…”

In Vitro Synergistic Interaction between DTA0100 and Radiation in Human Cancer Cell Lines

“…Additionally, it is well known that radiosensitivity changes with the progression of cells through the cell cycle, being the S phase most radioresistant and the G 2 /M phase most radiosensitive [4]. Preclinical CRT studies with taxanes [5], the marine-derived agent ET-743 [6], the human DNA topoisomerase IIα (TOP2) poisons etoposide [7] and GL331 [8], and the human DNA topoisomerase IIα catalytic inhibitors (TOP2-CIs) aclarubicin and ICRF-193 [9] resulted synergistic and provided proof of the concept. Among the diverse families of anticancer drugs that could be combined with RT, we have focused our attention on those able to arrest cells at the G 2 /M phase, which is claimed to be the most radiosensitive phase of the cell cycle [4].…”