Abstract. Multidrug resistance is one of the major causes limiting the efficacy of chemotherapeutic agents to control esophageal cancer. Herein, we investigated that the effect and mechanism of tetrandrine (TET) in the human esophageal squamous carcinoma cisplatin-resistant cell line YES-2/DDP. The human esophageal squamous carcinoma cisplatin-resistant cell line YES-2/DDP was isolated by stepwise selection in increasing concentrations of cisplatin. The CCK-8 method was carried out to measure the cell viability when cells were exposed to TET with or without cisplatin, and the IC 50 and resistance index (RI) of cisplatin was then calculated. Real-time RT-PCR and western blotting were used to detect the mRNA and protein expression of multidrug resistance 1 (MDR1), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP), respectively. Flow cytometry was adopted to determine CMFDA efflux and cell apoptosis, respectively. The resulting cell line YES-2/ DDP was 16.4-fold resistant to cisplatin, the cytotoxicity of cisplatin to YES-2/DDP cells was enhanced by TET in a dosedependent manner. Further, it was found that the expression of MDR1 and BCRP was similar in different treated cells. In contrast, the expression of MRP1 was markedly increased in YES-2/DDP cells, which was dose-dependently decreased by TET. In agreement with the results, MRP1 activity was also reversed by TET. In conclusion, TET possesses a reversal effect on drug resistance in YES-2/DDP cells through downregulation of MRP1, and has the potential to be an adjunct to chemotherapy for esophageal cancer. IntroductionChemotherapy is regarded as an important line of defense against esophageal cancer which is one of the most aggressive and lethal malignancies. However, on account of drug resistance especially multi-drug resistance (MDR), only a limited proportion of cancer patients respond favorably to commonly used chemotherapeutic drugs (1). With respect to the mechanisms of drug resistance, ATP-binding cassette (ABC) transporters, such as ABCB1/multidrug resistance 1 (MDR1), ABCC1/multidrug resistance-associated protein 1 (MRP1) and ABCG2/breast cancer resistance protein (BCRP), mediate energy-dependent drug efflux and play a main role in chemoresistance (2,3). Therefore, it seems imperative to find new drugs or methods especially targeting ABC transporters to reverse tumor drug-resistance.Tetrandrine (TET) (Fig. 1), a bis-benzylisoquinoline alkaloid isolated from the Chinese herb 'Han-Fang-Ji' (Radix Stephania tetrandra S. Moore), has been found to have immunosuppressive, free radical scavenging and anti-inflammatory activities (4-6). Furthermore, many recent studies have shown that TET exerts antitumor effects (7,8). In addition to inhibiting proliferation and inducing apoptosis of several cancer types, TET has exhibited potential as an adjunct to chemotherapy in many drug-resistant cancer cell lines (9,10). However, it remains unclear whether TET can reverse ABC transporter-mediated drug efflux. Moreover, it is als...
Background: N 6 -methyladenosine (m 6 A) methylation is dynamically regulated by writers and erasers, and ultimately affects RNA splicing, translation, and stability after by recognized readers, thereby affecting disease progression. Sunitinib (SUN) is a tyrosine kinase inhibitor (TKI) widely used to treat different types of solid and hematological tumors, but its cardiotoxicity limits its clinical application. FTO is an m 6 A demethylase has been shown to play an important role in various heart diseases. In this study, we deciphered the methylation modification of m 6 A mRNA in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) post sunitinib treatment and assessed whether FTO regulated pyroptosis-related m 6 A methylated transcripts in SUN-treated hiPSC-CMs. Methods and Results: The global m 6 A RNA-methylation level was increased in SUN-treated hiPSC-CMs and was parallel with a positively correlated cellular damage level (LDH leakage). Through a genome-wide analysis of m 6 A mRNA methylation by MeRIP-Seq and RNA-seq, we identified a total of 2614 peaks with significant changes. qRT-PCR, immunofluorescence, and Western blot revealed that FTO was the most evidently changed m 6 A modifying enzymes in SUN-treated hiPSC-CMs (downregulated fold change being 0.43). Interestingly, the loss of FTO in hiPSC-CMs exposed to SUN was positively associated with cellular damage level and pyroptosis- associated NLRP3 and ASC transcripts levels. To further test if TKI-induced increase in m 6 A-RNA modification is mediated through FTO loss, hiPSC-CMs, overexpressed with ectopic FTO, showed significant restoration of m 6 A methylation level and normalization of pyroptosis-associated transcripts (NLRP3 and ASC) after exposure to SUN. To evaluate the effect of FTO on the methylation of RNA transcripts of NLRP3 and ASC, MeRIP assay demonstrated that FTO tightly controlled the methylation levels of NLRP3 and ASC transcripts, and demethylation of these transcripts by FTO accelerated their degradation rate. Conclusion: This study revealed that TKI-induced loss of FTO may mediate the decreased m 6 A-RNA methylation and TKI-induced cardiotoxicity pathogenesis by dysregulating the methylation and expression of pyroptotic transcripts NLRP3 and ASC.
The interaction of dibazol to serum was investigated by fluorescence and UV-vis spectroscopy. The fluorescence experiment results show that the fluorescence of human serum can be effectively induced by light wave. The maximum fluorescence intensity of serum is excited at 280 nm and the peak wavelength is about 334 nm. It can also be concluded that the fluorescence intensity gradually increase with the increasing excitation light wavelength. The range of the fluorescence spectroscopy of serum-dibazol system induced by excited at different wavelength is about 290 - 450 nm. The fluorescence intensity of the interaction system of dibazol-serum is significantly reduced, indicating that the fluorescence quenching of serum occurred strongly caused by dibazol and there is a new compound formed between dibazol and serum. The absorption spectra show that there is a large blue in the system of dibazol and serum, which reveal that there is a kind of new complex between dibazol and serum. It is very significance to study the interaction between dibazol and serum for understanding of drug’s toxicity and its distribution in the organism.
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