CELLULAR ONCOLOGY
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2023
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IF 6.6
Wei Wanhui,Lu Yuanyuan,Hu Qian,Yin Jinwen,Wang Youwei,Zhang Heng,Zhao Qiu,Liu Lan
Purpose The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets. Methods First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC–MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay. Results Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis. Conclusions In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
·
IF 8.2
Xintao Gao,Yulan Yin,Shuai Liu,Kehong Dong,Jing Wang,Chuanlong Guo
Fucoidan (FU) is a natural polymer from marine organisms, which has been widely studied and applied in drug delivery. In this study, FU nanoparticles loaded with proanthocyanidins (PCs) (FU/PCs NPs) were prepared and their effect and mechanism in protecting cisplatin-induced acute kidney injury (AKI) were studied. The in vitro studies confirmed that FU/PCs NPs increased the antioxidant activity of free PCs and protected the death of human kidney proximal tubule (HK-2) cells induced by cisplatin. Further mechanism studies showed that FU/PCs NPs protected the mitochondrial damage induced by cisplatin, activated mitophagy, inhibited the release of mitochondrial DNA (mtDNA), and inhibited the cGAS/STING signal pathway. The in vivo results also indicated that FU/PCs NPs protected cisplatin-induced AKI, including inhibiting the increase of blood urea nitrogen (BUN) and serum creatinine (SCr) levels induced by cisplatin. The mechanism studies confirmed that cisplatin induced an increase in the expression of mitophagy-related protein Pink/Pakrin, mitochondrial mtDNA release and cGAS/STING expression in mice kidney tissues. Pre-administration of FU/PCs NPs further activated mitophagy, as well as inhibiting mtDNA release and cGAS/STING expression. In conclusion, our research proved the role of mitophagy-mtDNA-cGAS/STING signal was involved in cisplatin-induced AKI.
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LIFE SCIENCES
·
2023
·
IF 6.1
Haijie Wu,Xiaohu Shi,Yingda Zang,Xiaodi Zhao,Xikun Liu,Weida Wang,Wenying Shi,Clarence T.T. Wong,Li Sheng,Xiaoguang Chen,Sen Zhang
Aims Cisplatin is a widely-used drug in the clinical treatment of tumors, but kidney nephrotoxicity is one of the reasons that limits its widespread use. We previously found that 7-hydroxycoumarin-β-D-glucuronide (7-HCG) was one of metabolites of skimmin and highly enriched in the kidneys and maintained a high blood concentration in skimmin-treated rats. Therefore, we investigated whether 7-HCG has a protective effect on cisplatin-induced acute kidney injury. Materials and methods Male C57BL/6 mice were continuously administered 7-HCG for five days, and on the third day, an intraperitoneal injection of cisplatin was given to induce acute kidney injury. After 72 h, the mice were sacrificed for analysis. Serum and renal tissue were collected for renal function evaluation. RNA sequencing was used to explore mechanism, and further validated by western blot and immunohistochemistry. In addition, pharmacokinetic study of oral 7-HCG administration was performed to examine how much 7-hydroxycoumarin (7-HC) was metabolized and 7-HC possible effect on renal protection. Key findings 7-HCG significantly reduced serum BUN and SCR levels, and alleviated pathological damage in renal tissue, and reduced the renal index. RNA sequencing revealed that 7-HCG could reverse p38 MAPK regulation and apoptosis. By western blotting, it was found that 7-HCG could reduce renal injury by reducing p-p38, p-ERK, p-JNK, cleaved-caspase3 and Bax. The immunohistochemical results of cleaved-caspase3 were consistent with western blotting. 7-HCG also significantly reduced the production of ROS in kidney tissue. Pharmacokinetic experiments have shown that 7-HCG in the blood increased rapidly and was eliminated slowly, with an average t 1/2β of 18.3 h. And the concentration of 7-HCG in the target organ kidney was about 4 times higher than that in blood. Significance Our findings indicate that 7-HCG could exert its protective effect against cisplatin-induced acute kidney injury by inhibiting apoptosis via p38 MAPK regulation and elucidates its pharmacokinetics.
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International Journal of Nanomedicine
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2023
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IF 8
Muhammad Waseem Khan,Pengxuan Zhao,Asifullah Khan,Faisal Raza,Shahid Masood Raza,Muhammad Sarfraz,Yan Chen,Minsi Li,Tan Yang,Xiang Ma,Guangya Xiang
Background: Cisplatin (CDDP), a widely used chemotherapeutic agent against hepatocellular carcinoma (HCC), faces severe resistance and hepatotoxicity problems which can be alleviated through combination therapy.Purpose: The objective of this study was to develop a pH-dependent calcium carbonate nano-delivery system for the combination therapy of CDDP with oleanolic acid (OA).Methods: A microemulsion method was employed to generate lipid coated cisplatin/oleanolic acid calcium carbonate nanoparticles (CDDP/OA-LCC NPs), and the loading concentration of CDDP and OA was measured by atomic absorption spectroscopy and HPLC respectively.Transmission electron microscopy (TEM) was used to examine the nanoparticles morphology while its pH dependent release characteristics were investigated through in vitro release study. Cellular uptake was examined through a fluorescence microscopy. Apoptotic assays and western blot analysis were conducted to explore the synergistic apoptotic effect of OA on CDDP against HCC cells. The hepatoprotective of OA for CDDP was evaluated through H&E staining.Results: TEM analysis revealed nanoparticles spherical shape with an average particle size of 206±15 nm, and the overall entrapment efficiency was 63.70%±3.9%. In vitro drug release study confirmed the pH-dependent property of the formulation, with the maximum CDDP release of 70%±4.6% at pH 5.5, in contrast to 28%±4.1% CDDP release at pH 7.4. Annexin V-FITC/PI assay and cell cycle analysis confirmed that CDDP and OA synergistically promoted greater HepG2 cells apoptosis for the CDDP/OA-LCC NPs as compared to their individual free drug solutions and NPs-treated groups. Western blot analysis also proved that CDDP/OA-LCC NPs induced the apoptosis by enhancing the proapoptotic protein expressions through downregulating P13K/AKT/mTOR pathway and upregulating p53 proapoptotic pathway. OA helped CDDP to overcome the resistance by downregulating the expression of proteins like XIAP, Bcl-2 via NF-κB pathway. OA also significantly alleviated CDDP-induced hepatotoxicity as evident from the decreased alanine transaminase, aspartate transaminase levels and histochemical evaluation. The possible mechanism may be related to the Nrf-2 induction via its antioxidant mechanism to maintain the redox balance and reduction in CYP2E1 activity which can lead to ROS-mediated oxidative stress.Conclusion: These results suggest that CDDP/OA-LCC NPs have promising applications for co-delivering CDDP and OA to synergize their anti-tumor activity against HCC and to utilize OA’s protective effect against CDDP-induced hepatotoxicity.
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Cancer Biomarkers
·
2019
·Vol. 24
·期 4
·469-475
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IF 2.859
Qin Yujing,Li Wenxue,Long Yingli,Zhan Zhijia
OBJECTIVE: This study aims to determine the correlation between p-cofilin expression and cisplatin resistance in patients with ovarian cancer, and also to investigate the role of p-cofilin in prognosis. PATIENTS AND METHODS: The ovarian cancer cell line A2780/DDP resistant to cisplatin was prepared. The cell resistance to cisplatin was measured via MTT assay. The cell invasion capacity was identified via Transwell assay. The mRNA expression and protein level was evaluated via semi-quantitative PCR and Western blot, respectively. The tumor tissues of patients with cisplatin-resistant ovarian cancer were collected. The relationship between prognosis and p-cofilin expression was analyzed. RESULTS: The growth rate of A2780 was similar to that of A2780/DDP. The sensitivity of A2780 to cisplatin was significantly higher than that of A2780/DDP (p< 0.01). The migration capacity of A2780/DDP was significantly increased compared to that of A2780 (p< 0.01), indicating that the cisplatin-resistant cell lines were successfully constructed. Both CFL1 mRNA level and p-cofilin level in A2780/DDP was significantly higher than that in A2780 (p< 0.01). The p-cofilin level in cancer tissues in patients with cisplatin-resistant ovarian cancer was significantly higher than that in patients with cisplatin-sensitive ovarian cancer (p< 0.01). The cisplatin resistance was positively correlated with the p-cofilin expression level (r= 0.802, p= 0.023). The survival time of patients with normal or low level of p-cofilin was significantly longer than that of patients with high expression. CONCLUSION: The cisplatin resistance of ovarian cancer is closely related to the expression level of p-cofilin, which affects the prognosis of patients with ovarian cancer.
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MEDICINE
·
2018
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IF 2.028
Meijia Wu,Ting Huang,Juan Wang,Ping Chen,Wanwan Mi,Yuanyuan Ying,Hangli Wang,Dandan Zhao,Shengwu Huang
Supplemental Digital Content is available in the text
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TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE
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2025
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IF 1.6
Shaohao Luo,Yunfei Bai,Boqian Wang,Haixia Xu,Shu Zhang,Gang Guo,Xin Li,Hongyang Sun,Xiaobo Cui
Homeobox A1 (HOXA1) is implicated in the progression of various cancers, but its biological function in laryngeal cancer (LC) remains undefined, which is the foothold of our study. Bioinformatics analysis and survival analysis were performed to predict HOXA1 expression in LC tissues, and the prognostic relationship between high HOXA1 expression and LC. Whether high HOXA1 expression correlated with the clinical characteristics and prognosis of LC patients was analyzed. LC cell viability and sensitivity to cisplatin were determined by Methyl thiazolyl tetrazolium assay. The cell migration, invasion, and cell cycle after transfection were examined by Wound healing, Transwell, and flow cytometry assays, respectively. The corresponding mRNA and protein expressions were measured by quantitative real-time PCR or Western blot. A higher expression of HOXA1 was detected in LC tissues, which was found to be relevant to poor prognosis of LC patients. The association of high expression of HOXA1 with lymph node and clinical stage was also confirmed. Silencing of HOXA1 in LC cells enhanced the cell sensitivity to cisplatin, inhibited viability, migration, invasion and cell cycle, and reduced N-Cadherin, Vimentin, PCNA, p-AKT and p-mTOR expressions, while overexpression of HOXA1 had the opposite effects. Collectively, HOXA1 boosts migration, invasion and cell cycle, while suppressing cisplatin sensitivity of LC cells by mediating AKT/mTOR pathway, hinting that HOXA1 is a promising biomarker for diagnosis and prognosis of LC in clinical practice.
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FREE RADICAL BIOLOGY AND MEDICINE
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2024
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IF 7.1
Reziyamu Wufuer,Keli Liu,Jing Feng,Meng Wang,Shaofan Hu,Feilong Chen,Shanshan Lin,Yiguo Zhang
Cisplatin ( cis -Dichlorodiamineplatinum[II], CDDP) is generally accepted as a platinum-based alkylating agent type of the DNA-damaging anticancer drug, which is widely administrated in clinical treatment of many solid tumors . The pharmacological effect of CDDP is mainly achieved by replacing the chloride ion ( Cl − ) in its structure with H 2 O to form active substances with the strong electrophilic properties and then react with any nucleophilic molecules, primarily leading to genomic DNA damage and subsequent cell death. In this process, those target genes driven by the consensus electrophilic and/or antioxidant response elements (EpREs/AREs) in their promoter regions are also activated or repressed by CDDP. Thereby, we here examined the expression profiling of such genes regulated by two principal antioxidant transcription factors Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) in diverse cellular signaling responses to this intervention. The results demonstrated distinct cellular metabolisms, molecular pathways and signaling response mechanisms by which Nrf1 and Nrf2 as the drug targets differentially contribute to the anticancer efficacy of CDDP on hepatoma cells and xenograft tumor mice. Interestingly, the role of Nrf1, rather than Nrf2, is required for the anticancer effect of CDDP, to suppress malignant behavior of HepG2 cells by differentially monitoring multi-hierarchical signaling to gene regulatory networks . To our surprise, it was found there exists a closer relationship of Nrf1α than Nrf2 with DNA repair , but the hyperactive Nrf2 in Nrf1α –∕– cells manifests a strong correlation with its resistance to CDDP, albeit their mechanistic details remain elusive.
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BIOSENSORS & BIOELECTRONICS
·
2010
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IF 5.429
Shujun Ji,Qingqing Guo,Qiaoli Yue,Lei Wang,Huaisheng Wang,Jinsheng Zhao,Ruixin Dong,Jifeng Liu,Jianbo Jia
Fabrication of sub-monolayer array of Pt nanoparticles (PtNPs) assembled at nucleobases terminated layers and their application into H 2 O 2 and glucose sensing were reported. To prepare such a PtNPs assembly, 3-mercaptopropionic acid (MPA), Zr 4+ , nucleotide-5′-monophosphate (NTMP including guanosine, adenosine, cytidine, uridine-5′-monophosphate, and abbreviations were GMP, AMP, CMP, UMP, respectively) were adsorbed onto Au substrate sequentially to form nucleobases terminated surface and Zr 4+ acted as binder to link carboxylic and phosphoric groups (NTMP/Zr 4+ /MPA/Au). Complexation of cisplatin, cis-Pt(NH 3 ) 2 Cl 2 , with terminated nucleobases and following electrochemical reduction of surface-bound cisplatin gave PtNPs attached surface. Different PtNPs coverage or particle density was obtained depending on the NTMP used and decreased in the order: PtNPs/GMP/Zr 4+ /MPA/Au > PtNPs/AMP/Zr 4+ /MPA/Au > PtNPs/CMP/Zr 4+ /MPA/Au > PtNPs/UMP/Zr 4+ /MPA/Au. The surface loading of Pt was between 160 and 16 ng/cm 2 . The as prepared PtNPs can be used as electrocatalysts for H 2 O 2 sensing (detection limit of H 2 O 2 < 100 nM) and the sensitivity increased with decreasing PtNPs density. After adsorption of glucose oxidase, the modified electrode can be used as enzymatic electrode for glucose sensing and a detection limit of 38.5 μM was achieved. This study provided an example of fabricating PtNP arrays utilising surface complexation of cisplatin with nucleobases. The advantage of this method is that the NP density can be controlled through changing nucleobases or Pt complexes used to obtain suitable kinetics of the complexation reactions. Additionally, the PtNPs sub-monolayer as prepared has high sensitivity for H 2 O 2 sensing even at a very low loading of Pt.
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MACROMOLECULAR BIOSCIENCE
·
2016
·Vol. 17
·期 4
·1600262
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IF 3.68
Qin Yun,Si Song Wang,Shan Xu,Jin Ping Yang,Juan Fan,Ling Lin Yang,Yue Chen,Shao Zhi Fu,Jing Bo Wu
Colorectal peritoneal carcinomatosis (CRPC) is a common systemic metastasis of intra-abdominal cancers. Intraperitoneal chemotherapy against CRPC is at present the preferred treatment. The aim of this study is to develop a novel hydrogel drug delivery system through the combination of 5-fluorouracil (5-FU) loaded polymeric micelles and cisplatin (DDP) in biodegradable thermosensitive chitosan (CS) hydrogel. The prepared CS hydrogel drug is a free-flowing solution at room temperature and forms a stationary gel at body temperature. Therefore, a CRPC mouse model is established to investigate the antitumor activity of CS hydrogel drug system. The results suggest that intraperitoneal administration of CS hydrogel drug can inhibit tumor growth and metastasis, and prolong survival time compared with other groups, thus improving the chemotherapeutic effect. Ki-67 immunohistochemical analysis reveals that tumors in the CS hydrogel drug group has lower cell proliferation in contrast to other groups ( P < 0.001). Furthermore, hematoxylin-eosin staining of liver and lung tissue indicates that the CS hydrogel drug has also a certain inhibitory effect on colorectal cancer metastasis to the liver and lung. Hence, the work highlights the potential clinical applications of the CS hydrogel drug.
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MOLECULES
·
2020
·Vol. 25
·期 11
·2621
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IF 3.267
Xinli Guo,Zhou Fang,Min Zhang,Deyu Yang,Shuyue Wang,Kehai Liu
In order to enhance the sensitivity of drug-resistant ovarian cancer cells to cisplatin (DDP), a co-delivery system was designed for simultaneous delivery of curcumin (CUR) and p53 DNA. Firstly, the bifunctional peptide K14 composed of tumor targeting peptide (tLyP-1) and nuclear localization signal (NLS) was synthesized. A nonviral carrier (PEI-K14) was synthesized by cross-linking low molecular weight polyethyleneimine (PEI) with K14. Then, CUR was coupled to PEI-K14 by matrix metalloproteinase 9 (MMP9)-cleavable peptide to prepare CUR-PEI-K14. A co-delivery system, named CUR-PEI-K14/p53, was obtained by CUR-PEI-K14 and p53 self-assembly. Furthermore, the physicochemical properties and gene transfection efficiency were evaluated. Finally, ovarian cancer cisplatin-resistant (SKOV3-DDP) cells were selected to evaluate the effect of CUR-PEI-K14/p53 on enhancing the sensitivity of drug-resistant cells to DDP. The CUR-PEI-K14/DNA complexes appeared uniformly dispersed and spherical. The particle size was around 20–150 nm and the zeta potential was around 18–37 mV. It had good stability, high transfection efficiency, and low cytotoxicity. CUR-PEI-K14/p53 could significantly increase the sensitivity of SKOV3-DDP cells to DDP, and this effect was better as combined with DDP. The sensitizing effect might be related to the upregulation of p53 messenger RNA (mRNA), the downregulation of P-glycoprotein (P-gp) mRNA, and the upregulation of BCL2-Associated X (bax) mRNA. CUR-PEI-K14/p53 can be used as an effective strategy to enhance the sensitivity of drug-resistant ovarian cancer cells to DDP.Keywords:ovarian cancer;drug resistance;polyethyleneimine;curcumin;p53;co-delivery system
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American Journal of Translational Research
·
2025
·Vol. 17
·期 10
·8060
·
IF 1.6
Xia Tian,Zheng Han,Ye Yu,Jie Tan,Qingxi Zhu,Wei Chen,Shasha Huang,Xiaoli Chen,Meng Liu
Objective: To investigate the role of CDH17 in cisplatin (DDP) resistance in gastric cancer (GC) and to elucidate the potential molecular mechanisms. Methods: DDP-resistant GC cell lines were established, and CDH17 expression was silenced in these cells. Cell proliferation was assessed using the MTT assay. Cellular glycolytic activity was quantified, and apoptosis was assessed using flow cytometry. The expression of CDH17, β-catenin, key Warburg-related effector proteins, and Cleaved-caspase-3 was determined through molecular experiments. The Warburg effect inhibitor 2-DG and the Wnt/β-catenin signaling pathway agonist CP21R7 were applied to investigate the underlying molecular mechanism. Results: CDH17 was significantly upregulated in the DDP-resistant GC cells. CDH17 knockdown increased the sensitivity of GC cells to DDP, suppressed the Warburg effect, and inhibited the activation of the Wnt/β-catenin signaling pathway. Treatment with 2-DG reduced the chemoresistance in resistant GC cells. However, CP21R7 treatment promoted the Warburg effect in the DDP-resistant GC cells and partially attenuated the effects of CDH17 silencing on both the Warburg effect and DDP sensitivity. Conclusion: CDH17 silencing reversed DDP resistance in GC cells, primarily through inhibition of the Warburg effect mediated by the Wnt/β-catenin signaling pathway.
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