Carbazole-BODIPY dyes YHO-2 and YHO-3, which have diphenylamino-carbazole moiety as an electrondonating group at the 8-position on the BODIPY core, and heptanoic acid for YHO-2 and ethyl heptanoate for YHO-3 on the carbazole ring, were designed and synthesized and their photophysical properties in solution and in the solid state were investigated. Absorption and fluorescence properties of YHO-2 and YHO-3 are similar in solution, and both the dyes exhibited moderate fluorescence quantum yields.However, as-recrystallized dye YHO-3 exhibits solid-state red fluorescence but as-recrystallized dye YHO-2 exhibits feeble solid-state fluorescence properties. Interestingly, the dye YHO-3 possesses green metallic luster properties in both crystalline and amorphous states. Moreover, it was found that by grinding the as-recrystallized dye YHO-3, the disappearance of the metallic luster property and the blueshift of the fluorescence maximum were observed in the ground solid. On the basis of X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC), the solid-state photophysical properties of the carbazole-BODIPY dyes are discussed.Scheme 1 Synthesis of BODIPY dyes YHO-2 and YHO-3.
Cisplatin is an anticancer agent and induces DNA interstrand cross-links (ICLs). ICLs activate various signaling processes and induce DNA repair pathways, including the Fanconi anemia (FA) pathway. FA complementation group D2 (FANCD2) is monoubiquitinated in response to DNA damage, leading to activation of the DNA double-strand-break repair protein, RAD51. Caffeine increases the anticancer activity of cisplatin by inhibiting DNA repair; however, details of the mechanism remain unclear. We investigated the mechanism responsible for the synergistic anticancer effect of cisplatin and caffeine in HepG2 human hepatocellular carcinoma cells, focusing on the FA pathway. Caffeine (≥100 µg/mL) significantly enhanced the antiproliferative activity induced by 3.8 µg/mL cisplatin. Caffeine (200 µg/mL) promoted apoptosis and inhibited the increase in the proportion of viable cells in S phase that occurred in the presence of 3.8 µg/mL cisplatin. Both FANCD2 monoubiquitination and RAD51 expression were significantly inhibited by co-treatment with 200 µg/mL caffeine and 3.8 µg/mL cisplatin compared with cisplatin alone. In conclusion, caffeine enhances the anticancer effect of cisplatin by inhibiting FANCD2 monoubiquitination. In HepG2 cells, caffeine might inhibit the FA pathway and thereby regulate DNA damage responses such as DNA repair and apoptosis.
Key words caffeine; cisplatin; Fanconi anemia pathway; monoubiquitinationCisplatin is a platinum complex widely used for treating solid tumors.1) Its cytotoxic effects are the result of DNA interstrand cross-link (ICL) formation. Cisplatin ICLs are highly toxic DNA lesions that inhibit DNA strand separation.2)The homologous recombination (HR) DNA repair is induced by ICLs via the Fanconi anemia (FA) pathway.3) FA is a disease in which defective DNA repair leads to bone-marrow failure and the development of solid tumors, especially liver tumors.4) FA cells are hypersensitive to ICL-inducing agents, and FA pathway inhibition increases the anticancer effect of cisplatin.5) Therefore, the FA pathway plays an important role in repairing cisplatin-induced DNA damage.The FA pathway consists of at least 16 complementation groups and their associated genes. At least 10 FA proteins form the FA core complex, which mediates the monoubiquitination of FA complementation group D2 (FANCD2) at S phase of the cell cycle.6,7) Monoubiquitinated FANCD2 (FANCD2-Ub) is a key component of the FA pathway that functionally interacts with RAD51, which is essential for strand-pairing reactions during DNA recombination.
8)Caffeine is a methylxanthine alkaloid that is chemically related to the adenine and guanine bases of DNA and RNA. Caffeine increases the anticancer effect of cisplatin in hepatocellular carcinoma (HCC) cell lines via inhibiting DNA repair.9) In addition, a clinical trial of caffeine-potentiated chemotherapy previously reported positive results. 10) Caffeine suppresses HR by inhibiting both RAD51 accumulation and the activity of ataxia telangiectasia and Rad-3 related (ATR) kinase, which i...
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