Conjugation of Cisplatin Analogues and Cyclooxygenase Inhibitors to Overcome Cisplatin Resistance

SummaryThe relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency. Taken together, the results obtained with the drugs and with the fawn-hooded rats support the concept that ADP plays a key role in thrombogenesis in rats.

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The Effects of Modulation of Prostanoid Metabolism on the Thoracic Platelet Accumulation Induced by Intravenous Administration of Collagen in the Guinea-Pig

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661663 ◽

1986 ◽

Vol 56 (03) ◽

pp. 263-267

Author(s):

K D Butler ◽

R A Shand ◽

R B Wallis

Keyword(s):

Platelet Count ◽

Guinea Pig ◽

Intravenous Administration ◽

Cyclooxygenase Inhibitors ◽

Concomitant Increase ◽

Thromboxane Synthetase ◽

Platelet Accumulation ◽

Related Increase

SummaryThe effects of intravenously administered collagen on the circulatory platelet count, TxB2, 6-keto PGF1α and 51Cr-labelled platelet accumulation in the thorax have been evaluated in the guinea-pig. Administration of collagen induced a dose-related peripheral thrombocytopenia and a concomitant increase in 51Cr-labelled platelets in the thorax. There was also a transient dose-related increase in plasma TxB2 but no change in plasma 6-keto PGF1α levels.The thromboxane synthetase inhibitors tested, reduced the platelet accumulation, but only CGS 13080 significantly inhibited TxB2 production. In contrast all the cyclooxygenase inhibitors tested impaired the elevation of plasma TxB2 after collagen, but only diclofenac inhibited the 51Cr-labelled platelet accumulation.The greater effect of thromboxane synthetase inhibitors compared to cyclooxygenase inhibitors on platelet accumulation in this system cannot be completely explained by the changes measured in the circulating prostanoids.

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Reduced LINC00467 Elevates microRNA-125a-3p to Suppress Cisplatin Resistance in Non-Small Cell Lung Cancer Through Inhibiting Sirtuin 6 and Inactivating the ERK1/2 Signaling Pathway

SSRN Electronic Journal ◽

10.2139/ssrn.3572847 ◽

2020 ◽

Author(s):

Feng Xue ◽

Chuan Yang ◽

Keli Yun ◽

Cailing Jiang ◽

Rui Ca ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Signaling Pathway ◽

Cell Lung Cancer ◽

Cisplatin Resistance ◽

Small Cell ◽

Small Cell Lung

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3-MA Enhanced Chemosensitivity in Cisplatin Resistant Hypopharyngeal Squamous Carcinoma Cells via Inhibiting Beclin -1 Mediated Autophagy

Current Pharmaceutical Design ◽

10.2174/1381612826666201221150431 ◽

2020 ◽

Vol 26 ◽

Author(s):

Jia Zhang ◽

Wei Mao ◽

Yuying Liu ◽

Jian Ding ◽

Jie Wang ◽

...

Keyword(s):

Cell Cycle ◽

Squamous Cell Carcinoma ◽

Survival Rate ◽

Western Blot ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cisplatin Resistance ◽

Carcinoma Cells ◽

Fadu Cell ◽

Fadu Cells

Background: Hypopharyngeal carcinoma is characterized by high degree of malignancy. The most common pathological type is squamous cell carcinoma (HSCC). Cisplatin (cis-diamminedichloroplatinum, CDDP) is one of the most widely used chemotherapeutic drugs nowadays and cisplatin resistance is a major problem in current treatment strategies. Clinical researches have reported that high autophagy level often caused insensitivity to chemotherapy, a common phenomenon that greatly reduces therapeutic effect in cisplatin-resistant tumor cell lines. 3-methyladenine (3-MA), an inhibitor of PI3K, plays a vital role in the formation and development of autophagosomes. Therefore, we speculate that the use of 3-MA may reduce cisplatin resistance in hypopharyngeal squamous cell carcinoma (HSCC). Methods: Part I: Cisplatin-resistant FaDu cell line (Human hypopharyngeal squamous cell carcinoma cells) was established and cultured. Cell counting kit-8 was used to detect drug resistance. Inverted microscope was used to observe the morphological changes at different concentrations, then the survival rate was calculated. After MDC staining, the autophagic vacuoles were observed by fluorescence microscopy. The expression of Beclin1 from each group was confirmed by RTPCR and Western blot method. Part II: 3-MA was applied for cisplatin-resistant cells intervention, Beclin1 was knocked down by plasmid transfection. Cell cycle was detected using flow cytometry assay, apoptosis with necrosis was detected by staining with propidium iodide (PI). CCK-8 was used to observe the cell survival rate in each group. The expression of autophagy-related protein Beclin1, LC3I, LC3II, Atg-5 and P62 in each group was verified by Western blot analysis. Results: Cisplatin-resistant FaDu cell line can be stably constructed by cisplatin intervention. Compared with normal group, autophagy and its related protein Beclin1 expression was enhanced in cisplatin resistant FaDu cells. Autophagy inhibition group showed significant cell cycle changes, mainly manifested by G1 arrest, increased apoptosis rate and significantly decreased survival rate at 24h level. The number of autophagy vacuoles were significantly reduced in the 3-MA group. Furthermore, Western blot showed that expression of Beclin1, lc3-I, lc3-II, atg-5 protein decreased significantly after 3-MA intervention, while the expression of p62 up-regulated, which also confirmed autophagy flow was blocked. Conclusion: Our work confirmed that enhanced autophagy is an important cause of cisplatin resistance in FaDu cells. The use of 3-MA can significantly reduce autophagy level and arresting its cell cycle, promote apoptosis and reverse the cisplatin resistance condition, this effect is partly mediated by inhibition of Beclin-1 expression. Our data provides a theoretical basis for the application of 3-MA in overcoming cisplatin resistance in hypopharyngeal cancer.

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Molecular Mechanisms of Resistance in Testicular Germ Cell Tumors - clinical Implications

Current Cancer Drug Targets ◽

10.2174/1568009618666180102103959 ◽

2018 ◽

Vol 18 (10) ◽

pp. 967-978 ◽

Cited By ~ 8

Author(s):

Katarina Kalavska ◽

Vincenza Conteduca ◽

Ugo De Giorgi ◽

Michal Mego

Keyword(s):

Germ Cell ◽

Molecular Mechanisms ◽

Cisplatin Resistance ◽

Apoptotic Cell ◽

Germ Cell Tumors ◽

Treatment Resistance ◽

Experimental Models ◽

Testicular Germ Cell Tumors ◽

Testicular Germ Cell ◽

Repair Capacity

Testicular germ cell tumors (TGCTs) represent the most common malignancy in men aged 15-35. Due to these tumors’ biological and clinical characteristics, they can serve as an appropriate system for studying molecular mechanisms associated with cisplatin-based treatment resistance. This review describes treatment resistance from clinical and molecular viewpoints. Cisplatin resistance is determined by various biological mechanisms, including the modulation of the DNA repair capacity of cancer cells, alterations to apoptotic cell death pathways, deregulation of gene expression pathways, epigenetic alterations and insufficient DNA binding. Moreover, this review describes TGCTs as a model system that enables the study of the cellular features of cancer stem cells in metastatic process and describes experimental models that can be used to study treatment resistance in TGCTs. All of the abovementioned aspects may help to elucidate the molecular mechanisms underlying cisplatin resistance and may help to identify promising new therapeutic targets.

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UBE2L6 is Involved in Cisplatin Resistance by Regulating the Transcription of ABCB6

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200424130934 ◽

2020 ◽

Vol 20 (12) ◽

pp. 1487-1496 ◽

Cited By ~ 1

Author(s):

Midori Murakami ◽

Hiroto Izumi ◽

Tomoko Kurita ◽

Chiho Koi ◽

Yasuo Morimoto ◽

...

Keyword(s):

Gene Expression ◽

Promoter Activity ◽

Anticancer Agent ◽

Cisplatin Resistance ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Molecular Target ◽

Transcriptional Level ◽

And Control ◽

Resistant Cells

Background: Cisplatin is an important anticancer agent in cancer chemotherapy, but when resistant cells appear, treatment becomes difficult, and the prognosis is poor. Objective: In this study, we investigated the gene expression profile in cisplatin sensitive and resistant cells, and identified the genes involved in cisplatin resistance. Methods: Comparison of gene expression profiles revealed that UBE2L6 mRNA is highly expressed in resistant cells. To elucidate whether UBE2L6 is involved in the acquisition of cisplatin resistance, UBE2L6- overexpressing cells established from cisplatin-sensitive cells and UBE2L6-silenced cells developed from cisplatin- resistant cells were generated, and the sensitivity of cisplatin was examined. Results: The sensitivity of the UBE2L6-overexpressing cells did not change compared with the control cells, but the UBE2L6-silenced cells were sensitized to cisplatin. To elucidate the mechanism of UBE2L6 in cisplatin resistance, we compared the gene expression profiles of UBE2L6-silenced cells and control cells and found that the level of ABCB6 mRNA involved in cisplatin resistance was decreased. Moreover, ABCB6 promoter activity was partially suppressed in UBE2L6-silenced cells. Conclusion: These results suggest that cisplatin-resistant cells have upregulated UBE2L6 expression and contribute to cisplatin resistance by regulating ABCB6 expression at the transcriptional level. UBE2L6 might be a molecular target that overcomes cisplatin resistance.

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