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Adnan Khan Bushra Shal Ashraf Ullah Khan Rahim Ullah Muhammad Waleed Baig Ihsan ul Haq Eun Kyoung Seo Salman Khan 《International journal of molecular sciences》2021,22(11)
Vincristine (VCR) is a widely used chemotherapy drug that induced peripheral painful neuropathy. Yet, it still lacks an ideal therapeutic strategy. The transient receptor potential (TRP) channels, purinergic receptor (P2Y), and mitogen-activated protein kinase (MAPK) signaling play a crucial role in the pathogenesis of neuropathic pain. Withametelin (WMT), a potential Phytosteroid isolated from datura innoxa, exhibits remarkable neuroprotective properties. The present investigation was designed to explore the effect of withametelin on VCR-induced neuropathic pain and its underlying molecular mechanism. Initially, the neuroprotective potential of WMT was confirmed against hydrogen peroxide (H2O2)-induced PC12 cells. To develop potential candidates for neuropathic pain treatment, a VCR-induced neuropathic pain model was established. Vincristine (75 μg/kg) was administered intraperitoneally (i.p.) for 10 consecutive days (day 1–10) for the induction of neuropathic pain. Gabapentin (GBP) (60 mg/kg, i.p.) and withametelin (0.1 and 1 mg/kg i.p.) treatments were given after the completion of VCR injection on the 11th day up to 21 days. The results revealed that WMT significantly reduced VCR-induced pain hypersensitivity, including mechanical allodynia, cold allodynia, and thermal hyperalgesia. It reversed the VCR-induced histopathological changes in the brain, spinal cord, and sciatic nerve. It inhibited VCR-induced changes in the biochemical composition of the myelin sheath of the sciatic nerve. It markedly downregulated the expression levels of TRPV1 (transient receptor potential vanilloid 1); TRPM8 (Transient receptor potential melastatin 8); and P2Y nociceptors and MAPKs signaling, including ERK (Extracellular Signal-Regulated Kinase), JNK (c-Jun N-terminal kinase), and p-38 in the spinal cord. It suppressed apoptosis by regulating Bax (Bcl2-associated X-protein), Bcl-2 (B-cell-lymphoma-2), and Caspase-3 expression. It considerably attenuated inflammatory cytokines, oxidative stress, and genotoxicity. This study suggests that WMT treatment suppressed vincristine-induced neuropathic pain by targeting the TRPV1/TRPM8/P2Y nociceptors and MAPK signaling. 相似文献
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Tatiana Bubencíkova Dana Cholujová Lucia Messingerová Danica Mislovicova Mario Seres Albert Breier Zdena Sulova 《International journal of molecular sciences》2012,13(11):15177-15192
P-glycoprotein (P-gp) overexpression is the most frequently observed cause of multidrug resistance in neoplastic cells. In our experiments, P-gp was expressed in L1210 mice leukemia cells (S cells) by selection with vincristine (R cells) or transfection with the gene encoding human P-gp (T cells). Remodeling of cell surface sugars is associated with P-gp expression in L1210 cells as a secondary cellular response. In this study, we monitored the alteration of cell surface saccharides by Sambucus nigra agglutinin (SNA), wheat germ agglutinin (WGA) and Maackia amurensis agglutinin (MAA). Sialic acid is predominantly linked to the surface of S, R and T cells via α-2,6 branched sugars that tightly bind SNA. The presence of sialic acid linked to the cell surface via α-2,3 branched sugars was negligible, and the binding of MAA (recognizing this branch) was much less pronounced than SNA. WGA induced greater cell death than SNA, which was bound to the cell surface and agglutinated all three L1210 cell-variants more effectively than WGA. Thus, the ability of lectins to induce cell death did not correlate with their binding efficiency and agglutination potency. Compared to S cells, P-gp positive R and T cells contain a higher amount of N-acetyl-glucosamine on their cell surface, which is associated with improved WGA binding. Both P-gp positive variants of L1210 cells are strongly resistant to vincristine as P-gp prototypical drug. This resistance could not be altered by liberalization of terminal sialyl residues from the cell surface by sialidase. 相似文献
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添加5种不同浓度的辅酶类物质,根据单因素实验设计正交实验,研究其对抗肿瘤生物碱长春新碱合成的调控作用,并探讨其作用机理. 结果表明,单独添加每种辅酶类物质对长春新碱的合成均有促进作用,确定其最佳添加浓度为(mmol/L): DL-硫辛酸1.0, VB1 1.5, FMN 3.0, ATP 3.0,赖氨酸3.0,该条件下长春新碱合成量(细胞干重)为0.217 mg/g,为首次在长春花细胞培养中成功合成长春新碱. 相似文献
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An high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method for the determination of vinorelbine was presented, and the pharmacokinetics of the aqueous solution and lipid microspheres by intravenous were evaluated. Detection was performed using positive ion electrometry ionization followed by tandem mass spectrometry(ESI-MS/MS). The linear range of the standard curve of vinorelbine is from 1 to 1 000 μg•L-1. The method shows that it is specificity, convenient and suitable for assaying the concentration of vinorelbine in rat plasma, and is used to support pharmacologic studies with vinorelbine and preparation technology for lipid microspheres. 相似文献
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Yan Chen Xue-Lian Zheng Dai-Long Fang Yang Yang Jin-Kun Zhang Hui-Li Li Bei Xu Yi Lei Ke Ren Xiang-Rong Song 《International journal of molecular sciences》2014,15(2):2761-2772
Multidrug-resistant breast cancers have limited and ineffective clinical treatment options. This study aimed to develop PLGA nanoparticles containing a synergistic combination of vincristine and verapamil to achieve less toxicity and enhanced efficacy on multidrug-resistant breast cancers. The 1:250 molar ratio of VCR/VRP showed strong synergism with the reversal index of approximately 130 in the multidrug-resistant MCF-7/ADR cells compared to drug-sensitive MCF-7 cells. The lyophilized nanoparticles could get dispersed quickly with the similar size distribution, zeta potential and encapsulation efficiency to the pre-lyophilized nanoparticles suspension, and maintain the synergistic in vitro release ratio of drugs. The co-encapsulated nanoparticle formulation had lower toxicity than free vincristine/verapamil combinations according to the acute-toxicity test. Furthermore, the most effective tumor growth inhibition in the MCF-7/ADR human breast tumor xenograft was observed in the co-delivery nanoparticle formulation group in comparison with saline control, free vincristine, free vincristine/verapamil combinations and single-drug nanoparticle combinations. All the data demonstrated that PLGANPs simultaneously loaded with chemotherapeutic drug and chemosensitizer might be one of the most potential formulations in the treatment of multidrug-resistant breast cancer in clinic. 相似文献
7.
Xuan Gao Jun Zhang Qiang Xu Zun Huang Yiyue Wang 《Drug development and industrial pharmacy》2017,43(4):661-667
The goal of this research is to structure a hyaluronic acid modified nanostructured lipid carrier (HA-NLCs) for vincristine sulfate (VCR) delivery, and detect its efficiency to improve the oral bioavailability. Emulsion solvent evaporation method was used to prepare the HA-NLCs nanoparticles. The particle size, zeta potential and entrapment efficiency of VCR-NLCs and HA-NLCs were 187?±?3.52?nm, ?8.61?±?1.29?mV, 33.12?±?1.16% and 192?±?4.41?nm, ?32.82?±?2.64?mV, 34.41?±?2.21%, respectively. HA-NLCs could significantly improve the cellular uptake efficiency and cytotoxicity in MCF-7 cells than other VCR formulations. The expressions of apoptosis related protein Caspase-3, Caspase-9, Bax and Bcl-2 were estimated by western blot assay in MCF-7 cells, and HA-NLCs exhibited the strongest effect in promoting cell apoptosis. The pharmacokinetics of HA-NLCs was evaluated in Sprague–Dawley male rats and the relative oral bioavailability of HA-NLCs and VCR-NLCs was improved about 1.8-fold and two-fold compared with VCR solution, respectively. Therefore, these results indicated that HA-NLCs could significantly improve the oral bioavailability and was a promising vehicle for the oral delivery of VCR. 相似文献
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Silvia Triarico Alberto Romano Giorgio Attin Michele Antonio Capozza Palma Maurizi Stefano Mastrangelo Antonio Ruggiero 《International journal of molecular sciences》2021,22(8)
Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients and an increase in medical costs. Vincristine acts out its antineoplastic function by altering the normal assembly and disassembly of microtubules, with their consequent mitosis block and death. Vincristine leads to VIPN through a complex mechanism of damage, which occurs not only on the microtubules, but also on the endothelium and the mitochondria of nerve cells. Furthermore, both patient-related risk factors (age, race, ethnicity and genetic polymorphisms) and treatment-related risk factors (dose, time of infusion and drug–drug interactions) are involved in the pathogenesis of VIPN. There is a lack of consensus about the prophylaxis and treatment of VIPN among pediatric oncologic patients, despite several molecules (such as gabapentin, pyridoxine and pyridostigmine, glutamic acid and glutamine) having been already investigated in clinical trials. This review describes the molecular mechanisms of VIPN and analyzes the risk factors and the principal drugs adopted for the prophylaxis and treatment of VIPN in pediatric patients with cancer. 相似文献
10.
长春新碱透皮给药系统筛选及其透皮机理研究 总被引:3,自引:0,他引:3
分别制备了含不同表面活性剂的载长春新碱传递体(VCR-T)和载长春新碱壳聚糖纳米粒(VCR-CS-NPs),通过体外透皮试验,比较了不同透皮给药系统的透皮效果,并用DSC扫描探索了透皮效果差异的原因.所制备的VCR-T包封率从50%至80%不等,粒径90nm左右;VCR-CS-NPs的包封率为50%,粒径200nm左右;透射电镜下观察VCR-T和VCR-CS-NPs均外形圆整光滑,不粘连.体外透皮结果显示含Brij78的VCR-T为最佳的VCR透皮给药系统,DSC扫描认为这与载体与Brij78的相互作用有关;VCR-CS-NPs不能很好地透过皮肤,这可能与其粒径较大有关. 相似文献