• Biomolecules & Therapeutics
• /
• 제1권1호
• /
• pp.44-49
• /
• 1993

cis-Dichlorodiammineplatinum(cisplatin) is one of the most effective antitumor agents currently available for cancer therapy. However, its clinical use has been limited by its severe side effects, especially nephrotoxicity. So, to evaluate the effects of 2(3)-tert-butyl-4-hydroxyanisole(BHA) on cisplatin nephrotoxicity in rats, both compounds were given intraperitoneally. Remarkable protective effects of BHA against nephrotoxicity of cisplatin were observed when BHA was administered to rats 1hr after cisplatin injection. On the other hand pretreatment with BHA 1hr prior to cisplatin did not reduce weight loss, blood urea nitrogen and creatinine levels. Hepatotoxicity induced by combination treatment of cisplatin and BHA was evaluated by measuring serum glutamic pyruvate transaminase and serum glutamic oxalate transaminase. Combination treatment did not affect the levels of SGPT and sGOT except 1hr pretreatment. The present results indicate that BHA may provide protection against cisplatin nephrotoxicity, when it is given 1hr after cisplatin.

• Environmental Analysis Health and Toxicology
• /
• 제13권3_4호
• /
• pp.125-131
• /
• 1998

Cisplatin is one of the most effective antitumor agents currently available for cancer chemotherapy. However its clinical use has been limited by its severe side effects, especially nephrotoxicity. To evaluate the effect of schizandrin, one of radical scavengers and constituents of Schizandra chimensis, cisplatin and schizandrin were given intraperitoneally. Protective effect of schizandrin against nephrotoxicity of cisplatin was observed when schizandrin was administerd to rats 1,24 hr after cisplatin injection. Hepatotoxicity induced by combination treatment of cisplatin and schizandrin was evaluated by measuring sGPT and sGOT. Combination treatment did not affect the levels of sGPT and sGOT. The present result indicate that schizandrin when it is given after cisplatin, may provide protection against cisplatin nephrotoxicity without hepatotoxicity.

• 동의생리병리학회지
• /
• 제21권4호
• /
• pp.992-997
• /
• 2007

Cisplatin is a chemotherapeutic drug which is widely used for cancer therapy including cervical cancer. The purpose of this study is to elucidate synergistic effect of Cisplatin and Berberine on the apoptosis of HeLa cells and to determine whether oxidants are formed as part of apoptotic process. Apoptotic death of HeLa cells by cisplatin and berberine was confirmed by chromatin condensation of HeLa cells and flow cytometric analysis of intracellular ROS(reactive oxygen species) production. In MTT assay, Cell viability was decreased and enhanced ROS generation in combination of cisplatin and berberine significantly, as compared with cisplatin only. Synergistic effect of Cisplatin and Berberine on the inhibition of cell growth by apoptosis was clearly observed and ROS may play an important role in apoptosis. This effect suggest the possibility lowering the concentration of chemotherapeutic drugs, which alleviate the side effect of drugs.

• The Korean Journal of Physiology and Pharmacology
• /
• 제11권2호
• /
• pp.71-77
• /
• 2007

Cisplatin treatment increases the excretion of inorganic phosphate in vivo. However, the mechanism by which cisplatin reduces phosphate uptake through renal proximal tubular cells has not yet been elucidated. We examined the effect of cisplatin on $Na^+$-dependent phosphate uptake in opossum kidney (OK) cells, an established proximal tubular cell line. Cells were exposed to cisplatin for an appropriate time period and phosphate uptake was measured using $[^{32}P]$-phosphate. Changes in the number of phosphate transporter in membranes were evaluated by kinetic analysis, $[^{14}C]$phosphonoformic acid binding, and Western blot analysis. Cisplatin inhibited phosphate uptake in a time- and dose-dependent manner, and also the $Na^+$-dependent uptake without altering $Na^+$-independent uptake. The cisplatin inhibition was not affected by the hydrogen peroxide scavenger catalase, but completely prevented by the hydroxyl radical scavenger dimethylthiourea. Antioxidants were ineffective in preventing the cisplatin-induced inhibition of phosphate uptake. Kinetic analysis indicated that cisplatin decreased Vmax of $Na^+$-dependent phosphate uptake without any change in the Km value. $Na^+$-dependent phosphonoformic acid binding was decreased by cisplatin treatment. Western blot analysis showed that cisplatin caused degradation of $Na^+$-dependent phosphate transporter protein. Taken together, these data suggest that cisplatin inhibits phosphate transport in renal proximal tubular cells through the reduction in the number of functional phosphate transport units. Such effects of cisplatin are mediated by production of hydroxyl radicals.

• 동의생리병리학회지
• /
• 제21권6호
• /
• pp.1555-1563
• /
• 2007

To idenifty effect of Bojungbangam-tang kakambang on Cisplatin-Induced G2/M Phase Arrest in Human Renal Proximal Tubular HK-2 Cells. Cytotoxicity of cisplatin was detected in HK-2 cells and the value of IC50 is about $25\;{\mu}M$. The treatment of cisplatin to HK-2 showed the G2/M phase cell cycle arrest. The ethanol extract of Bojungbangam-tang kakambang (EBTKB), a new herbal prescription composed of ten crude herbs, inhibited cisplatin-induced G2/M phase arrest in HK-2 cells. EBTKB increased G0/G1 peak in cisplatin-treated HK-2 cells. p53, p21 and p27 expression were increased in cisplatin-treated HK-2 cells. Inhibitory effect of EBTKB on cisplatin-induced G2/M phase arrest was accomplished through inhibition of p53, p21 and p27 expression. Also, reduced CDK2 and cyclin A expression by cisplatin were increased by EBTKB, but cyclin E was not changed. Reduction of ERK activation and increment of p38 activation by cisplatin were increased ERK activation and decreased p38 activation by EBTKB. Cisplatin had no effect on JNK activation, but EBTKB increased JNK activation. These results can suggest that EBTKB inhibits cisplatin-induced G2/M phase arrest in HK-2 cell through reduction of p53-dependent p21 and p27 protein, ERK activation and p38 inactivation.

• BMB Reports
• /
• 제56권6호
• /
• pp.347-352
• /
• 2023

The protein family of poly (ADP-ribose) polymerases (PARPs) is comprised of multifunctional nuclear enzymes. Several PARP inhibitors have been developed as new anticancer drugs to combat resistance to chemotherapy. Herein, we characterized PARP4 mRNA expression profiles in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines. PARP4 mRNA expression was significantly upregulated in cisplatin-resistant ovarian cancer cell lines, and this upregulation was associated with the hypomethylation of specific cytosine-phosphate-guanine (CpG) sites (cg18582260 and cg17117459) on its promoter. Reduced PARP4 expression was restored by treating cisplatin-sensitive cell lines with a demethylation agent, implicating the epigenetic regulation of PARP4 expression by promoter methylation. Depletion of PARP4 expression in cisplatin-resistant cell lines reduced cisplatin chemoresistance and promoted cisplatin-induced DNA fragmentation. The differential mRNA expression and DNA methylation status at specific PARP4 promoter CpG sites (cg18582260 and cg17117459) according to cisplatin responses, was further validated in primary ovarian tumor tissues. The results showed significantly increased PARP4 mRNA expressions and decreased DNA methylation levels at specific PARP4 promoter CpG sites (cg18582260 and cg17117459) in cisplatin-resistant patients. Additionally, the DNA methylation status at cg18582260 CpG sites in ovarian tumor tissues showed fairly clear discrimination between cisplatin-resistant patients and cisplatin-sensitive patients, with high accuracy (area under the curve = 0.86, P = 0.003845). Our findings suggest that the DNA methylation status of PARP4 at the specific promoter site (cg18582260) may be a useful diagnostic biomarker for predicting the response to cisplatin in ovarian cancer patients.

• 동의생리병리학회지
• /
• 제17권2호
• /
• pp.394-402
• /
• 2003

This study was designed to investigate the protective effect of Bojungmyunyuk-dan(BJMY-Dan) on the cisplatin-induced cytotoxicity of primary rat astrocytes. BJMY-Dan is an oriental herbal prescription for its ability to recover protective effects against anti-cancer chemotherapies. After astrocytes were treated cisplatin, MTT assay was performed for cell viability test. To explore the mechanism of cytotoxicity, I used the several measures of apoptosis to determine whether this processes was involved in cisplatin-induced cell damage in astrocytes. Also, astrocytes were treated with BJMY-Dan and then, followed by the addition of cisplatin. Cisplatin decreased the viability of astrocytes in a dose and time-dependent manner. BJMY-Dan increased the viability of astrocytes treated cisplatin. Astrocytes treated cisplatin were revealed as apoptosis characterized by nuclear staining and flow cytometry. BJMY-Dan protected astrocytes from cisplatin-induced nuclear fragmentation and chromatin condensation. Also, caspase-3 and caspase-9 proteases were activated in astrocytes by cisplatin. BJMY-Dan inhibited the activation of caspase proteases in cisplatin-treated astrocytes. Cleavage of [poly(ADP-ribose) polymerase](PARP) was occurred at 12hr after treatment of cisplatin in astrocytes. BJMY-Dan recovered the cleavage of PARP in cisplatin-treated astrocytes. Also, BJMY-Dan inhibited the activation of pro-apoptotic factor, Bak by cisplatin. Lastly, astrocytes stained with JC-1 and Rhodamine 123 were photographed by fluorescence microscope to visualize changes of mitochondrial membrane permeability transition(MPT) during treatment with cisplatin for 24hr. BJMY-Dan recovered the change of MPT by cisplatin in astrocytes. According to above results, BJMY-Dan may protect astrocytes from cytotoxicity induced by chemotherapeutic agents, including cisplatin.

• Radiation Oncology Journal
• /
• 제16권2호
• /
• pp.125-138
• /
• 1998

목적 : 흰쥐의 전뇌에 방사선조사 후 cis-diamminedichloroplatinum(II)(cisplatin)을 복강내 주입하여 cisplatin이 방사선에 의한 후기 뇌손상(3개월, 6개월)에 미치는 효과를 알기 위하여 이 연구를 시행하였다. 방법 및 재료 : 흰쥐를 방사전조사군, cisplatin군, 방사선조사와 cisplatin 병용군으로 분류하였다. 방사선조사군은 선형가속기를 사용하여 20 Gy, 22.5 Gy의 x-ray를 각각 횐쥐의 전뇌에 단일조사하였다. Cisplatin군은 2, 4, 8mg/kg을 각각 복강내에 1회 주입하였다. 병용군은 방사선조사(20 Gy, 22.5 Gy) 후 즉시 cisplatin(2mg/kg)를 복강내에 1회 주입하였다. 각 군에 따라 치료 후 3개월과 6개월에 동물을 희생시키고 뇌의 조직병리학적 검사를 시행하였다. 결과 : Cisplatin군은 맥락총에 상피성 공포형성과 혈관주위의 부종 및 혈관의 확장이 3개월에 보였으며, 채상과 대뇌반구에 다원성 괴사가 3개월과 6개월에 나타났다. 방사선조사군과 병용군에서 뇌의 후기 방사선손상의 특징인 국소적 응고성 괴사와 혈관의 변화가 현저하게 나타났으며 현저한 혈관주위와 연수막에 성상세포의 증식은anti-GFAP 항체검사로 확인되었다. 방사선조사에 의한 혈관변화와 성상세포의 증식이 cisplatin에 의해서 증가되지는 않았다. 결론 : Cisplatin과 방사선조사에 의한 후기 뇌손상의 변화로 국소적 괴사가 양군에서 동시에 나타남으로서 뇌손상의 정도를 추정하는데 괴사가 지표인자로 이용될 수 있다고 본다. Cisplatin이 방사선에 의한 혈관의 변화와 성상세포의 증식에는 영향을 미치지 않았으므로, 뇌에서 cisplatin과 방사선의 상호작용을 파악하기 위해서는 향후 더 많은 실험이 필요하다.

• 생명과학회지
• /
• 제18권4호
• /
• pp.542-549
• /
• 2008

Cisplatin은 임상적으로 다양한 종류의 종양 치료에 사용되는 중요한 항암제 중의 하나이다. 그러나 cisplatin은 이독성, 신장독성, 골수독성, 위장독성 및 말초신경독성 등의 심각한 부작용으로 인하여 사용이 제한적이다. Cisplatin에 의한 청각장애에서 organ of Corti 외측 유모세포(outer hair cells) 손상이 유발한다. Cisplatin에 의한 세포독성에 대한 연구가 진행 중이지만 pro-inflammatory cytokine과 관련된 청각세포사멸에 대한 연구는 미비하다. 이 연구에서 cisplatin은 청각세포주 HEI-OC1 세포와 렛트 cochlear explant에서 염증성 사이토카인인 $TNF-{\alpha}$, $IL-1{\beta}$ 및 IL-6의 유전자 발현과 분비를 현저히 증가시켰다. 이들 염증성 사이토카인은 organ of Corti 청각유모세포에 직접적인 세포독성을 나타내어 외측 및 내측 유모세포와 배열을 파괴하였다. 염증반응에서 중요한 $TNF-{\alpha}$를 cisplatin을 처리한 실험군에서 immunocytochemistry를 통하여 관찰 한 결과 organ of Corti에서의 발현이 현저히 증가됨을 관찰하였다. 염증성 사이토카인에 대한 중화항체를 처리하여 cisplatin에 의한 세포독성이 현저히 감소됨을 HEI-OC1 세포와 청각유모세포에서 확인하였다. 또한 GSH, NAC와 같은 항산화제를 처리하여 세포독성이 현저히 감소됨을 확인하였다. 이상의 결과는 cisplatin에 의한 청각유모세포의 죽음에서 $TNF-{\alpha}$, $IL-1{\beta}$ 및 IL-6와 같은 염증성 사이토카인이 병리 생리학적으로 중요한 역할을 하고 있음을 시사한다.

• Journal of Acupuncture Research
• /
• 제34권3호
• /
• pp.39-48
• /
• 2017

Objectives : The objective of this study was to evaluate the effect of Dokhwaljihwang-tang (DJT) intravenous pharmacopuncture on cisplatin-induced emesis and gastric mobility disorder in Wistar rats. Methods : Thirty rats were randomly divided into six groups and cisplatin was administered to all groups except the normal group. The cisplatin group (n=5) received a cisplatin injection only. The saline group (n=5) was injected with cisplatin followed by 0.4 mL of saline. Groups DJT-1, DJT-2, and DJT-3 were injected with cisplatin, followed by 0.315 g/kg, 0.104 g/kg, and 0.034 g/kg of DJT, respectively. Body weight, food intake, and kaolin intake of rats were measured 12 h, 24 h, and 36 h after cisplatin injection. Residual food in the stomach was measured 48 h after cisplatin injection. Results : There was no significant difference in weight. The food intake was not significantly different 12 h after cisplatin administration. All groups except the normal group showed significantly decreased food intake after 24 h. After 36 h, food intake was not significantly different between groups DJT-1, DJT-2, and DJT-3 and the normal group. The kaolin intake of groups DJT-1 and DJT-2 was significantly decreased at 12 h and 24 h after cisplatin injection. Kaolin intake and residual food in the stomach were significantly decreased in groups DJT-1, DJT-2, and DJT-3. Conclusion : In a Wistar rat model, DJT intravenous pharmacopuncture is suggested to be effective for cisplatin-induced emesis and gastric motility disorder. In the future, it is necessary to study the mechanism and chemical composition of each individual constitutive drug.