Optimized two‐dimensional gel electrophoresis in an alkaline pH range improves the identification of intracellular CFDA‐cisplatin‐protein adducts in ovarian cancer cells

Intracellular binding of cisplatin to proteins has been associated with acquired resistance to chemotherapy. In our previous study we established an analytical method for the identification of intracellular cisplatin‐binding proteins. The method used a fluorescent carboxyfluorescein‐diacetate‐labeled cisplatin analogue (CFDA‐cisplatin), two‐dimensional gel electrophoresis (2DE) and mass spectrometry, which allows detecting and identifying intracellular CFDA‐cisplatin‐containing protein adducts in the acidic pH range (pH 4–7). Based on this analytical method we extended the identification of intracellular cisplatin‐protein adducts to the alkaline pH range (pH 6–10) giving chance to discover new important binding partners. 2DE analysis of alkaline proteins is challenging due to the difficult separation of basic proteins during the isoelectric focusing (IEF). The establishment of an optimized IEF protocol for basic proteins enabled us to identify several intracellular CFDA‐cisplatin‐binding proteins including enzymes of the glucose and serine metabolism like alpha enolase and D‐3‐phosphoglycerate 1‐dehydrogenase.     

A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance

DNA damage response plays a key role not only in maintaining genome integrity but also in mediating the antitumor efficacy of DNA‐damaging antineoplastic drugs. Herein, we report the rational design and evaluation of a Pt^IV anticancer prodrug inhibiting nucleotide excision repair (NER), one of the most pivotal processes after the formation of cisplatin‐induced DNA damage that deactivates the drug and leads to drug resistance in the clinic. This dual‐action prodrug enters cells efficiently and causes DNA damage while simultaneously inhibiting NER to promote apoptotic response. The prodrug is strongly active against the proliferation of cisplatin‐resistant human cancer cells with an up to 88‐fold increase in growth inhibition compared with cisplatin, and the prodrug is much more active than a mixture of cisplatin and an NER inhibitor. Our study highlights the importance of targeting downstream pathways after the formation of Pt‐induced DNA damage as a novel strategy to conquer cisplatin resistance.     

[Bis(aminomethyl)dimethylsilane]platinum(II) dichloride: A potential antitumor agent

[Bis(aminomethyl)dimethylsilane]platinum(II) dichloride (1) was synthesized by a three-step procedure. The antitumor activity of 1 was evaluated in the i.p. implanted mouse L1210 leukemia model. A 10 mg kg^?1 dose administered every fourth day for a total of three injections extended the median life span of the dying mice by at least 100% and resulted in 40–50% survivors (day 30) in two experiments corresponding to an approximate 6 log₁₀ reduction in tumor burden at the end of treatment. Compound 1 appeared at least as active as cisplatin under the testing protocols utilized. The closely related bis[aminomethyltrimethylsilane]platinum(II) dichloride complex was inactive in this mouse model.     

Hydration process as an activation of trans- and cisplatin complexes in anticancer treatment. DFT and ab initio computational study of thermodynamic and kinetic parameters

The thermodynamic and kinetic aspects of hydration reactions of cis-/transplatin were explored. The polarizable continuum model was used for estimation of solvent effects. Using the B3LYP/6-31+G(d) method, the structures were optimized and vibrational frequencies estimated. Interaction energies and activation barriers were determined at the CCSD(T)/6-31++G(d,p) level within the COSMO approach. An associative mechanism was assumed with a trigonal-bipyramidal structure of the transition state. Within the applied model, all the hydration reactions are slightly endothermic. The Gibbs energies of cisplatin hydration amount to 7.0 and 14.2 kcal/mol for the chloride and ammonium replacement, respectively. Analogous values for the transplatin reactions are 6.8 and 11.9 kcal/mol. The determined rate constants are by several (three to four) orders of magnitude larger for the dechlorination process than for deammination. The cisplatin dechlorination rate constant was established as 1.3 x 10(-4) s(-1) in excellent accord with the experiment.     

平衡透析法研究顺铂与多核苷酸的作用

用平衡透析法研究了37℃,pH=7(或5)离子强度为0.1条件下(0.01mol·dm~(-3)磷酸盐缓冲体系),顺式二氯二氨合铂(顺铂)与多鸟苷酸、多腺苷酸以及多胞苷酸之间的相互作用.用McGhec和von Hippel法对实验数据进行分析,求得其结合常数,反映键合过程中顺铂分子间相互作用的协同参数以及每个顺铂分子所键合的核苷酸残基数.并讨论了顺铂与多核苷酸的键合方式.     

石墨烯纳米载药体系的制备及对人口腔鳞癌细胞杀伤效果

利用化学氧化还原法制备了氧化石墨烯,进一步超声破碎剥离,得到纳米氧化石墨烯,并对其进行聚乙二醇(PEG)的功能化修饰后载药顺铂。 采用扫描电子显微镜(SEM)、紫外-可见吸收光谱(UV-Vis)、傅立叶变换红外光谱(FTIR)对石墨烯纳米载药体系进行表征,细胞存活率实验(MTT)法检验石墨烯纳米载药体系对人口腔鳞癌(KB)细胞的杀伤作用。 结果表明,石墨烯纳米载药体系对顺铂的负载率为42.4%,聚乙二醇修饰后可以降低纳米氧化石墨烯的细胞毒性并提高生物相容性,对KB细胞具有双重的杀伤作用,为纳米氧化石墨烯在肿瘤治疗的临床应用提供了理论依据。     

cis-Diamminodichloronickel and Its Interaction with Guanine and Guanine–Cytosine Base Pair

Comprehensive ab initio calculations are performed on cis-diamminodichloronickel (cisni) at the HF, DFT, and MP2 levels of theory. The results are compared to those obtained for cisplatin. The characteristics of the interactions of cisni with guanine (G) and guanine–cytosine (GC) base pair are also evaluated and compared to the interactions of cisplatin. Cisni causes similar geometric changes of the base as cis-platinum when complexed to guanine. The nickel, palladium and platinum complexes also show similar characteristics when complexed to GC base pair. However, this study predicts higher dissociation energy of the cisni chlorine ligands that indicate areas of differences between the title Ni and Pt and Pd complexes. Comparison of the G-cisni interaction energy to that of cisplatin and cispd indicate differences between the Ni and Pd complexes, but also reveals its closer similarities to cisplatin.