single drug treatment; 0 01 < p < 0 05 (*, †, #), 0 001 < p < 0 0

single drug treatment; 0.01 < p < 0.05 (*, †, #), 0.001 < p < 0.01 (**, ††, ##), p < 0.001 (***, †††, ###)). There was a high inhibition of cell proliferation after single and combined treatments with SBI-0206965 chemical structure protons and DTIC, as compared to control cells (***, p < 0.001), and is given in Figure 2B. The effects of combined treatments were stronger than those of relevant single treatments, particularly regarding DTIC (†, p < 0.05; ††, p < 0.01 and ###, p < 0.001). LY411575 in vitro A reduction of cell survival vs. control,

as it is shown in Figure 2C, was obtained after single proton irradiation or combination of protons and DTIC (***, p < 0.001) and was in the same range. Single DTIC treatment provoked negligible cell inactivation. The effects of protons and FM or DTIC on cell cycle distribution Compared to untreated controls, proton irradiation of HTB140 cells induced a dose dependent increase of G1 cell population. FM

provoked a raise of G2 phase followed by a reduction of S phase with some changes in G0/G1 cell population. After combined treatments with protons and FM, there was an improvement of S and G2 phase followed by a decrease of G0/G1 cell population (Figure 3A). It appears that the major Smad inhibitor characteristic of combined treatment with respect to single protons or FM was an increase of S phase mostly compensated by a reduction of G0/G1 phase. Figure 3 Cell cycle analyses after single and combined treatments. Cell cycle analysis of HTB140 cells estimated by flow cytometry, after single and combined treatments with protons and FM (A) or protons and DTIC (B). Irradiation doses were 12 (I) and 16 (II) Gy, while drug concentrations were 100 (III) and 250 μM (IV). The percentage of cells in G0/G1, S and G2/M phase were obtained with the XL SYSTEM II software. Single DTIC treatment did not provoke changes in the cell cycle distribution as compared to control. It differed from proton effects by an increase in S and G2 cell population. Cell cycle distribution after combined application of protons and DTIC remained in the range Tideglusib of controls and single DTIC effects (Figure

3B). Discussion Radio- and chemoresistance of malignant melanoma can be related to the phenotypic heterogeneity, including different degrees of cellular pigmentation, diverse cell morphology and growth rate of variety of melanoma types [17, 18]. It has been shown that when using conventional radiation, the common radiosensitivity parameter, the surviving fraction at 2 Gy of different melanoma cell lines ranged from 0.36 to 0.96 [16, 19, 20]. The HTB140 human melanoma cells are among cell lines with the highest values, thus representing the limit case of cellular radioresistance. To increase the inactivation level these cells were irradiated with protons that have higher linear energy transfer than conventional radiation. Still, the surviving fraction at 2 Gy remained high with the value of 0.93 [16].

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