Cisplatin-treated Group Research Articles

Euphorbia helioscopia inhibits proliferation, invasion, and migration and promotes apoptosis of non-small cell lung cancer cells

To investigate the effect of Euphorbia helioscopia on biological behaviors of non-small cell lung cancer (NSCLC) cells. NSCLC cell lines PC-9 and A549 treated with different concentrations of Euphorbia helioscopia preparations were examined for changes in proliferation, apoptosis, invasion and migration using CCK-8 assay, colony formation assay, flow cytometry, wound healing assay and Transwell assay. Western blotting was performed to detect the changes in protein expressions of Bax, Bcl-2, E-cadherin, vimentin, MMP2, and MMP9 in the treated cells. PC-9 cells were injected subcutaneously into BALB/C nude mice to establish a nude mouse subcutaneous tumor model. According to the growth of subcutaneous tumors, mice were randomly divided into control group: gavaged daily with saline; Euphorbia helioscopia-treated group: gavaged daily with Euphorbia helioscopia 65 mg/mL, and Euphorbia helioscopia granules were dissolved in saline; cisplatin-treated group: injected intraperitoneally with cisplatin 4 mg/kg every 5 days, 6 mice per group. The subcutaneous tumor volume and mass changes of mice were measured, and the toxic effects of Euphorbia helioscopia on heart, liver, spleen, lung and kidney as well as the therapeutic effects of Euphorbia helioscopia were observed in the mice bearing tumor. Euphorbia helioscopia granules concentration-dependently inhibited the proliferation and survival of PC-9 and A549 cells, significantly promoted cell apoptosis, suppressed invasion and migration abilities of the cells, up-regulated the expression levels of E-cadherin and Bax, and down-regulated the expressions of Bcl-2, vimentin, MMP2, and MMP9. In the tumor-bearing mice, treatment with Euphorbia helioscopia significantly inhibited tumor growth without producing obvious toxicity in the vital organs. Euphorbia helioscopia can inhibit proliferation, invasion, and migration and induces apoptosis of NSCLC cells in vitro.

The therapeutic potential of 1, 25-dihydroxy vitamin D3 on cisplatin-affected neurological functions is associated with the regulation of oxidative stress and inflammatory markers as well as levels of MMP2/9.

Calcitriol as a biologically active form of vitamin D3 has beneficial effects on all body systems. This vitamin has a potent neuroprotective effect via several independent mechanisms against brain insults induced by anticancer drugs. The present study was designed to examine the neuroprotective effects of calcitriol against neurotoxicity induced by cisplatin.Induction of neurotoxicity was done with cisplatin administration (5mg/kg/week) for 5 successive weeks in male Wistar rats. The neuroprotective influence of calcitriol supplementation (100ng/kg/day for 5 weeks) was assessed through behavioral, electrophysiological, and molecular experiments.Cisplatin administration impaired spatial learning and memory and decreased prefrontal brain-derived neurotrophic factor (BDNF). Peripheral sensory neuropathy was induced through cisplatin administration. Cisplatin also reduced the amplitudes of the compound action potential of sensory nerves in electrophysiological studies. Cisplatin treatment elevated MDA levels and reduced anti-oxidant (SOD and GPx) enzymes. Pro-inflammatory cytokines (IL-1β and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were augmented through treatment with cisplatin. Learning and memory impairments along with BDNF changes caused by cisplatin were amended with calcitriol supplementation. Reduced sensory nerve conduction velocity in the cisplatin-treated group was improved by calcitriol. Calcitriol partially improved redox imbalance and diminished the pro-inflammatory cytokines and MMP-2/9 levels.Our findings showed that calcitriol supplementation can relieve cisplatin-induced peripheral neurotoxicity. Calcitriol can be regarded as a promising new neuroprotective agent.

Probing the Effects of Retinoblastoma Binding Protein 6 (RBBP6) Knockdown on the Sensitivity of Cisplatin in Cervical Cancer Cells.

Cervical cancer is a major cause of death in women despite the advancement of current treatment modalities. The conventional therapeutic agent, cisplatin (CCDP), is the standard treatment for CC; however, resistance often develops due to the cancer's heterogeneity. Therefore, a detailed elucidation of the specific molecular mechanisms driving CC is crucial for the development of targeted therapeutic strategies. Retinoblastoma binding protein 6 (RBBP6) is a potential biomarker associated with cell proliferation and is upregulated in cervical cancer sites, exhibiting apoptosis and dysregulated p53 expression. Furthermore, RBBP6 has been demonstrated to sensitize cancer cells to radiation and certain chemotherapeutic agents by regulating the Bcl-2 gene, thus suggesting a crosstalk among RBBP6/p53/BCL-2 oncogenic signatures. The present study, therefore, investigated the relationship between cisplatin and RBBP6 expression in CC cells. Herein, we first explored bioinformatics simulations and identified that the RBBP6/p53/BCL-2 signaling pathway is overexpressed and correlated with CC. For further analysis, we explored the Genomics of Drug Sensitivity in Cancer (GDSC) and found that most of the CC cell lines are sensitive to CCDP. To validate these findings, RBBP6 was silenced in HeLa and Vero cells using RNAi technology, followed by measurement of wild-type p53 and Bcl-2 at the mRNA level using qPCR. Cells co-treated with cisplatin and siRBBP6 were subsequently analyzed for apoptosis induction and real-time growth monitoring using flow cytometry and the xCELLigence system, respectively. Cancer cells in the co-treatment group showed a reduction in apoptosis compared to the cisplatin-treated group. Moreover, the real-time growth monitoring revealed a reduced growth rate in RBBP6 knockdown cells treated with cisplatin. Although wild-type p53 remained unchanged in the co-treatment group of cancer cells, Bcl-2 was completely repressed, suggesting that RBBP6 is necessary for sensitizing cervical cancer cells to cisplatin treatment by downregulating Bcl-2. The Vero cell population, which served as a non-cancerous control cell line in this study, remained viable following treatment with both siRBBP6 and cisplatin. Findings from this study suggest that RBBP6 expression promotes cisplatin sensitivity in HeLa cells through Bcl-2 downregulation. Knockdown of RBBP6 limits apoptosis induction and delays cell growth inhibition in response to cisplatin. The knowledge obtained here has the potential to help improve cisplatin efficacy through personalized administration based on the expression profile of RBBP6 among individual patients.

Ondansetron attenuates cisplatin-induced behavioral and cognitive impairment through downregulation of NOD-like receptor inflammasome pathway

Cisplatin is an effective and commonly used chemotherapeutic drug; however, its use is accompanied by several adverse effects, including chemobrain. Ondansetron is a 5-HT3 antagonist, commonly used in prophylactic against chemotherapy-induced nausea and vomiting. Moreover, it has been identified as a novel neuroprotective agent in different animal models. However, its protective role against chemotherapy-induced chemobrain has not been investigated. The current study was the first study that explored the potential neuroprotective effect of ondansetron against cisplatin-induced chemobrain in rats. Cisplatin (5 mg/Kg) was injected intraperitoneally, once weekly, for 4 weeks with the daily administration of ondansetron (0.5 and 1 mg/Kg). Compared to the cisplatin-treated group, ondansetron administration showed a significant decrease in the latency time and a significant increase in ambulation, rearing, and grooming frequency in the open field test (OFT). Moreover, a significant improvement in the latency time in the rotarod and passive avoidance tests, following ondansetron administration. In addition, ondansetron treatment increased the percentage of alternation in the Y-maze test. Also, ondansetron showed a remarkable enhancement in the biochemical parameters in the hippocampus. It increased the acetylcholine (Ach) level and decreased the level of the acetylcholine esterase enzyme (AchE). Ondansetron significantly decreased interleukin-1β (Il-1β), tumor necrosis factor-alpha (TNF-α), toll-like receptor-4 (TLR-4), NOD-like receptor-3 (NLRP3) inflammasome as well as caspase-1 and caspase-3 levels. Furthermore, ondansetron significantly decreased the levels of copper transporter-1(CTR1) expression in the hippocampus. Collectively, these findings suggest that ondansetron may exhibit a neuroprotective and therapeutic activity against cisplatin-induced chemobrain.

Fulvestrant alleviates cisplatin-induced acute kidney injury via repression of BNIP3-mediated apoptosis and autophagy.

Cisplatin-induced acute kidney injury (AKI) is a clinical disease characterized by a sudden loss of renal function within a few hours or days, due to cisplatin uptake. Fulvestrant is an oestrogen receptor alpha (ERα) antagonist used for endocrine therapy. However, the role of fulvestrant in cisplatin-induced AKI remains unclear. In this study, we investigated the effects of fulvestrant on the regulation of apoptotic cell death and autophagic response in cisplatin-induced AKI. The human kidney proximal tubule epithelial cell line (HK-2) was co-treated with fulvestrant and cisplatin. C57BL/6 mice were subcutaneously injected with fulvestrant and cisplatin was administered via intraperitoneal injection. First, cisplatin treatment increased ERα expression, apoptosis, and autophagy in HK-2 cells. Fulvestrant treatment decreased apoptosis and autophagy, which were accompanied by cisplatin treatment in HK-2 cells. Consistent with in vitro results, cisplatin treatment significantly increased ERα expression in vivo. Additionally, cisplatin treatment increased renal injury, apoptosis, and autophagy. Surprisingly, compared to that in the cisplatin-treated mice group, reduced cisplatin-induced renal injury, apoptosis, and autophagy was observed in the cisplatin+fulvestrant-treated mice group. In summary, these results suggest that fulvestrant plays an important role in cisplatin-induced AKI by decreasing apoptosis and autophagy.

Valproic acid treatment attenuates cisplatin-induced kidney injury by suppressing proximal tubular cell damage.

Cisplatin treatment is effective against several types of carcinomas. However, it frequently leads to kidney injury, which warrants effective prevention methods. Sodium valproic acid is a prophylactic drug candidate with a high potential for clinical application against cisplatin-induced kidney injury. Therefore, in this study, we aimed to elucidate the mechanism underlying the prophylactic effect of valproic acid on cisplatin-induced kidney injury in a mouse model and HK2 and PODO cells with cisplatin-induced toxicity. In the mouse model of cisplatin-induced kidney injury, various renal function parameters and tubular damage scores were worsened by cisplatin, but they were significantly improved upon combination with valproic acid. No difference was observed in cisplatin accumulation between the cisplatin-treated and valproic acid-treated groups in whole blood and the kidneys. The mRNA expression levels of proximal tubular damage markers, apoptosis markers, and inflammatory cytokines significantly increased in the cisplatin group 72 h after cisplatin administration but significantly decreased upon combination with valproic acid. In HK2 cells, a human proximal tubular cell line, the cisplatin-induced decrease in cell viability was significantly suppressed by co-treatment with valproic acid. Valproic acid may inhibit cisplatin-induced kidney injury by suppressing apoptosis, inflammatory responses, and glomerular damage throughout the kidneys by suppressing proximal tubular cell damage. However, prospective controlled trials need to evaluate these findings before their practical application.

Downregulation of PGC-1α during cisplatin-induced muscle atrophy in murine skeletal muscle

This study aimed to investigate the effects of cisplatin on adenosine triphosphate (ATP) levels, expressions of genes related to mitochondrial oxidative phosphorylation (OXPHOS), and the factors related to mitochondrial biosynthesis in skeletal muscle. Systemic cisplatin administration decreased skeletal muscle mass, skeletal muscle strength, and endurance. The mitochondrial DNA /nuclear DNA ratio was also reduced after treatment with cisplatin. Moreover, among the factors related to mitochondrial biogenesis and function, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was significantly downregulated in the cisplatin-treated group. Downregulation of PGC-1α in the skeletal muscle may contribute to muscle weakness during cisplatin-induced muscle atrophy.

Diagnostic potential of serum miR-532-3p as a circulating biomarker for experimental intrinsic drug-induced liver injury by acetaminophen and cisplatin in rats.

Evaluating tissue injury largely depends on serum biochemical analysis despite insufficient tissue specificity and low sensitivity. Therefore, attention has been paid to the potential of microRNAs (miRNAs) to overcome the limitations of the current diagnostic tools, as tissue-enriched miRNAs are detected in the blood upon tissue injury. First, using a cisplatin-injected rats, we screened a specific pattern of altered hepatic miRNAs and their target mRNAs. Subsequently, we identified novel liver-specific circulating miRNAs for drug-induced liver injury by comparing miRNA expression changes in organs and serum. RNA sequencing revealed that 32 hepatic miRNAs were differentially expressed (DE) in the cisplatin-treated group. Furthermore, among the 1217 targets predicted using miRDB on these DE-miRNAs, 153 hepatic genes involved in different liver function-related pathways and processes were found to be dysregulated by cisplatin. Next, comparative analyses of the liver, kidneys, and serum DE-miRNAs were conducted to select circulating miRNA biomarker candidates reflecting drug-induced liver injury. Finally, among the four liver-specific circulating miRNAs selected based on their expression patterns in tissue and serum, miR-532-3p was increased in the serum after cisplatin or acetaminophen administration. Our findings suggest that miR-532-3p is potential as a serum biomarker for identifying drug-induced liver injury, leading to the accurate diagnosis.

Protective Effect of Platelet-Rich Plasma on Cisplatin-Induced Nephrotoxicity in Adult Male Albino Rats: Histological and Immunohistochemical Study.

Cisplatin is a potent antineoplastic drug that is used for treatment of many solid tumors. It has a wide range of adverse effects. Nephrotoxicity is the most common one of them. Platelet-rich plasma (PRP) is an autologous human plasma that activates the tissue regeneration through cell proliferation and differentiation. Study the role of PRP in amelioration of cisplatin-induced nephrotoxicity on the kidney of adult male albino rats by biochemical, morphometric, histological, and immunohistochemical studies. Thirty-five adult male albino rats were used. Thirty rats were included as experimental group and five were used to obtain the PRP. The experimental group was classified into as follows: control group which received 1mL of sterile saline by intraperitoneal injection (IP), cisplatin-treated group which received cisplatin 7.5 mg/kg IP in a single dose and cisplatin and PRP-treated group rats received cisplatin 7.5 mg/kg single IP dose followed by 1ml of PRP IP after 24 h of cisplatin injection. There was a significant increase in urea and creatinine levels in cisplatin-treated group in comparison to the control and the PRP groups. The kidneys of cisplatin-treated group showed distorted renal structure, where specimens of PRP-treated group revealed restoration of the classical appearance of the renal tissue similar to the control group. PRP has protective effects on renal structure and functions and it helps to ameliorate the histological changes induced by cisplatin.

Yi-Shen-Xie-Zhuo formula alleviates cisplatin-induced AKI by regulating inflammation and apoptosis via the cGAS/STING pathway.

Yi-Shen-Xie-Zhuo formula (YSXZF) is a traditional Chinese medicine prescription developed from the classic prescription Mulizexie powder documented in the book of Golden Chamber Synopsis and the Buyanghuanwu Decoction recorded in the book of Correction of Errors in Medical Classics. According to our years of clinical experience, YSXZF can effectively improve qi deficiency and blood stasis in kidney disease. However, its mechanisms need further clarification. Apoptosis and inflammation play key roles in acute kidney disease (AKI). The Yi-Shen-Xie-Zhuo formula, consisting of four herbs, is commonly used for treating renal disease. However, the underlying mechanism and bioactive components remain unexplored. This study aimed to investigate the protective effects of YSXZF against apoptosis and inflammation in a cisplatin-treated mouse model, and identify the main bioactive components of YSXZF. C57BL/6 mice were administered cisplatin (15mg/kg) with or without YSXZF (11.375 or 22.75g/kg/d). HKC-8cells were treated with cisplatin (20μM) with or without YSXZF (5% or 10%) for 24h. Renal function, morphology, and cell damage were evaluated. UHPLC-MS was used to analyze the herbal components and metabolites in the YSXZF-containing serum. Blood urea nitrogen (BUN), serum creatinine, serum and urine neutrophil gelatinase-associated lipocalin (NGAL) levels were clearly increased in the cisplatin-treated group. Administration of YSXZF reversed these changes; it improved renal histology, downregulated kidney injury molecule 1 (KIM-1) expression, and lowered the number of TdT-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells. YSXZF significantly downregulated cleaved caspase-3 and BAX, and upregulated BCL-2 proteins in renal tissues. YSXZF suppressed increase in cGAS/STING activation and inflammation. In vitro treatment with YSXZF markedly reduced cisplatin-induced HKC-8cell apoptosis, relieved cGAS/STING activation and inflammation, improved mitochondrial membrane potential (MMP), and lowered reactive oxygen species (ROS) overgeneration. Small RNA interference (siRNA)-mediated silencing of cGAS or STING inhibited the protective effects of YSXZF. Twenty-three bioactive constituents from the YSXZF-containing serum were identified as key components. This is the first study to demonstrate that YSXZF protects against AKI by suppressing inflammation and apoptosis via the cGAS/STING signaling pathway.

Protective effects of esomeprazole against cisplatin-induced ototoxicity: an in vitro and in vivo study

In this study, we aimed to identify novel compounds that could afford protection against cisplatin-induced ototoxicity by employing both cell- and zebrafish (Danio rerio)-based screening platforms. We screened 923 US Food and Drug Administration-approved drugs to identify potential compounds exhibiting protective effects against cisplatin-induced ototoxicity in HEI-OC1 cells (auditory hair cell line). The screening strategy identified esomeprazole and dexlansoprazole as the primary hit compounds. Subsequently, we examined the effects of these compounds on cell viability and apoptosis. Our results revealed that esomeprazole and dexlansoprazole inhibited organic cation transporter 2 (OCT2), thus providing in vitro evidence that these compounds could ameliorate cisplatin-induced ototoxicity by directly inhibiting OCT2-mediated cisplatin transport. In vivo, the protective effects were validated using zebrafish; esomeprazole was found to decrease cisplatin-induced hair cell damage in neuromasts. Furthermore, the esomeprazole-treated group showed a significantly lower number of TUNEL-positive cells than the cisplatin-treated group. Collectively, our findings revealed that esomeprazole exerts a protective effect against cisplatin-induced hair cell damage in both HEI-OC1 cells and a zebrafish model.

Creatine Chemical Exchange Saturation Transfer (Cr-CEST) Imaging Can Evaluate Cisplatin-induced Testicular Damage.

This study aimed to investigate the ability of creatine-chemical exchange saturation transfer (Cr-CEST) technique assessed through 7-T MRI to evaluate cisplatin-induced testicular damage. We used 8-10 weeks C57BL/6 mice (n = 10) that were divided into a control group (n = 5) and a cisplatin-treated group (n = 5). The cisplatin group received cisplatin at a dose of 15 mg/kg, via intraperitoneal injection, while the control group received saline. MR images of mouse testes were acquired under anesthesia 18 days after the injection using a horizontal 7-T scanner. The pulse sequence consisted of rapid acquisition with a relaxation enhancement (RARE) with magnetization transfer. The Z-spectra were collected using a 2000-ms saturation pulse at a B1 amplitude of 1.2 μT, with frequencies varying from -4.8 to +4.8 parts per million (ppm). Maps of magnetization transfer ratio with asymmetric analysis (MTRasym) were reconstructed at a Cr metabolite concentration of 1.8 ppm. The Cr-CEST effect was significantly reduced in the cisplatin-treated group compared to the control group (MTRasym of control mice vs. cisplatin-treated mice: 6.9 [6-7.5] vs. 5.2 [4-5.5], P = 0.008). Correlation analysis revealed a strong correlation between the Cr-CEST effect and the pathological score (ρ = 0.93, P < 0.001). Cr-CEST MRI can be useful for the evaluation of cisplatin-induced testicular damage in mice.

Melatonin Mitigates Cisplatin-Induced Ovarian Dysfunction via Altering Steroidogenesis, Inflammation, Apoptosis, Oxidative Stress, and PTEN/PI3K/Akt/mTOR/AMPK Signaling Pathway in Female Rats.

Ovarian damage and fertility impairment are major side effects of chemotherapy in pre-menopausal cancer patients. Cisplatin is a widely used chemotherapeutic drug. The present study was designed to assess the ameliorative effects of melatonin as an adjuvant for fertility preservation. Thirty-two adult female Wistar rats were divided randomly into four equal groups: Control, Melatonin, Cisplatin (CP) treated, and CP + Melatonin treated. The cisplatin-treated group showed decreased body and ovarian weights, decreased serum E2 and AMH, increased serum LH and FSH, reduced ovarian levels of SOD, CAT, GSH, and TAC, and increased ovarian MDA. The histopathological examination of the cisplatin-treated group showed deleterious changes within ovarian tissue in the form of damaged follicles and corpus luteum, hemorrhage, and inflammatory infiltrates with faint PAS reaction in zona pellucida, increased ovarian collagen deposition, and marked expression of caspase-3 immune reaction in granulosa and theca cells, stroma, and oocytes. Alongside, there was a significant downregulation in the mRNA expression of steroidogenic enzymes, IL10, AMPK, PI3K, AKT, mTOR, and PTEN, while TGF-β1, IL1β, IL6, TNF-α, NF-Kβ, P53, p38-MAPK, JNK, and FOXO3 mRNA expressions were upregulated in cisplatin-treated rats' ovarian tissue. Coadministration of cisplatin-treated rats with melatonin reversed these changes significantly. In conclusion, melatonin's antioxidant, anti-inflammatory, and anti-apoptotic activities could modulate ovarian disturbances induced by cisplatin and preserve fertility.

The Effect of Honey (Apis Mellifera) Fermentation On Cisplatin Induced Hepatic Histology of Rats and The Review According to Islamic Perspective

Background: Cancer is one of the main killer diseases in the world. Cancer must be treated properly. The most common cancer treatment is chemotherapy. Cisplatin is one of the chemotherapy drugs used because of its wide efficacy for the treatment of various types of cancer. Side effects of cisplatin include ototoxicity, nephrotoxicity, hepatotoxicity, neurotoxicity and bone marrow depression. Therefore, there is a need for a solution that can reduce the side effects of cisplatin. One of the natural ingredients that can reduce the side effects of cisplatin is honey. Methods: This research is in the form of primary data, the data is taken directly by conducting an in vivo experiment. This study was divided into 4 groups, namely the untreated group, the cisplatin treatment group only, the cisplatin treatment group with 5% honey fermentation and the cisplatin treatment group with 10% honey fermentation. After that, HE staining was performed to see the histopathological picture of liver cells. Results: Fermentation of honey can reduce the size of congestion and hemorrhage from liver cells exposed to cisplatin. Conclusion: Fermented honey can protect the liver from the toxic effects of cisplatin exposure. In the view of Islam, treatment is one of the efforts in getting the gift of healing from Allah Subhanahu wa Ta'ala. Islam and medicine agree on the importance of this research to support the goals of Islamic law, namely Maqashid Syari'iyah.

Barhi date (Phoenix dactylifera) extract ameliorates hepatocellular carcinoma in male rats

Hepatocellular carcinoma (HCC) is a malignant tumor with limited treatment options. Given this fact, it may be important to develop new molecular targeted therapies from natural products, especially those which are primary sources of effective anticancer drugs with distinct mechanisms. Moreover, the complementary use of traditional herbs or fruit may increase the possibility of finding curative options for cancer. Here we explore the anticancer effects and possible molecular mechanism of Barhi date extract using an HCC rat model. Thirty two male albino rats were arbitrarily allocated into four groups: a negative control group (NCG); a positive control group (PCG), which received CCl4 (1 ml/kg b.wt./ i.p.) twice a week for three months; a Barhi date extract (400 mg/kg b.wt./day/orally) treatment group (DTG) during the third month of CCl4 administration; and a cisplatin (1.5 mg/kg b.wt./ i.p.) treatment group ( CTG) during the third month of CCl4 administration. After treatment we performed biochemical analyses of all groups to assess relative eukaryotic initiation factor 2 alpha (eIF2α), extracellular signal-regulated kinases (ERKs), protein kinase RNA-like endoplasmic reticulum kinase (PERK), poly (ADP-ribose) polymerase (PARP), and CASPASE 3 protein content, and examined expression of the genes phosphatase and tensin homolog (PTEN) and protein kinase B (AKT). We also performed an immunohistochemistry assay for alpha-fetoprotein (AFP). Our data showed higher PARP and CASPASE3 levels and liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) in the PCG compared to the DTG and the cisplatin treatment group CTG. However, we also found a significant decrease in PTEN in the PCG relative to both the DTG and the CTG. We conclude that the anti-tumor activity of Barhi date extract may be mediated by the inhibition of cell proliferation and apoptosis via the ERK /PARP/caspase3 pathway and the AKT/ PTEN signaling pathways.

Oroxylum indicum stem bark extract exerts antitumor potential against Ehrlich’s ascites carcinoma in Swiss albino mice

Introduction and Aim: Constant efforts are exerted to explore unique bioactive principles from natural sources that possess more effective and specific antineoplastic activities. In the present study, we aimed to evaluate the antitumor activity of stem bark extract of Oroxylum indicum in mice bearing Ehrlich ascites carcinoma (EAC). Materials and Methods: Ninety female Swiss albino mice were categorized into fifteen groups (n=6). The animals were inoculated with 1x106 EAC cells. Tumor control animals received sterile water once daily for 10 consecutive days. Positive control group was injected with Cisplatin (CP) (one dose – 3.5 mg/kg body weight). The treatment groups were administered with O. indicum (OI) stem bark ethanol extract once daily with 50mg/kg, 200mg/kg and 400mg/kg body weight for eleven consecutive days. The blood parameters and serum hepatic enzymes activity was determined. The percentage increase in weight, the median survival time, the increase in median life span was calculated. The cytotoxic effect of CP and OI extract was determined. Results: There was significant reduction in the white blood cells count in OI and CP treatment group compared to increased level in EAC control group. The RBC count and Hemoglobin level which was significantly decreased (p&lt;0.05) in the tumour mice, was enhanced in the drug treatment groups. The EAC control group showed significant increase in tumour cell count (p&lt;0.05) whereas, treatment of EAC tumor bearing mice with OI and CP significantly increased the non-viable tumor cell count (p&lt;0.05). Conclusion: OI stem bark ethanol extract reduced the toxic implications of Ehrlich ascites carcinoma, reverted the haematological and biochemical changes induced by tumour. These results call for additional research on isolating and identifying the responsible bioactive elements in order to clarify the underlying processes of the anticancer impact.

Transcriptomic responses to cytotoxic drug cisplatin in water flea Daphnia magna

Cytotoxic drugs have been recognized by the European Union as the potential threat in the aquatic environment. As a typical cytotoxic drug, effects of long-term exposure to cisplatin at the environmentally relevant concentrations on the crustacean health and its molecular mechanism remain undetermined. In this study, the growth and reproduction of Daphnia magna resulting from cisplatin exposure were initially assessed. While the phenotypes were not altered in 2 μg L−1, 20 μg L−1, and 200 μg L−1 treatment groups, cisplatin at 500 µg L−1 significantly reduced the offspring number to 8–13 neonates in each brood, which was lower than 13–27 neonates in the control group. In addition to the delay in the time of first pregnancy, the body length was decreased by approximate 12.13% at day 7. Meanwhile, all daphnids died after exposure to 500 µg L−1 cisplatin for 17 days. Transcriptome profiling bioassays were performed for 10 days to explore the alternation at the molecular level. Briefly, 980 (257 up- and 723 down-regulated), 429 (182 up- and 247 down-regulated) and 1984 (616 up-regulated and 1368 down-regulated) genes were differentially expressed (adj p < 0.05) in low (2 μg L−1), medium (200 μg L−1) and high (500 μg L−1) cisplatin treatment groups, respectively. Differentially expressed genes were primarily enriched in the digestion and absorption, nerve conduction, endocrine interference, and circulatory related pathways. Specifically, the down-regulated digestive secretion and nutrient absorption and neuronal conduction pathways may lead to insufficient energy supply involved in growth and reproduction, and hinder ovarian development and cell growth. Down-regulation of ovarian steroids and relaxin signaling pathways may be related to the reduction of offspring number and delayed pregnancy, and reduced body length of D. magna may attribute to the enrichment of insulin secretion pathway. In addition, the death of D. magna may result from the reduced expression of genes in cardiomyocyte contraction and apoptosome processes. Taken together, this study revealed the potential toxic mechanism of cisplatin in a model water flea.

Abstract 5478: EC-18 suppressed tumor growth and alleviated side effects caused by cisplatin in the HNSCC implantation model

Abstract Introduction: Head and neck squamous cell carcinomas (HNSCC) are very unfavorable carcinoma that lowers the quality of life. In addition, side effects associated with treatment such as oral mucositis also deteriorate enough to be classified as a disease. This study verified the synergistic antitumor effect of EC-18 (PLAG, 1-Palmitoyl-2-linoleoyl-3-acetyl-roc-glycerol) with or without cisplatin as a chemotherapy and side effects alleviation effects in the metastatic mouse oral squamous carcinoma (MOSCC) orthotopic model. Method: After inserting mouse-derived squamous oral carcinoma into the right side of the tongue (n=12), it was treated with EC-18 alone or with cisplatin for three weeks. The changes in feed rate and body weight were quantitatively verified on a 2-day interval. Changes in tumor size and oral mucositis symptoms (toluidine-blue positive) were analyzed on the sacrifice day. In addition, changes in the amount of damage-associated molecular pattern (DAMP) increased by tumor and cisplatin, and changes in related active factors were quantitatively analyzed. Result: Compared to the positive control group, the tumor size was reduced by 42% in the group treated with EC-18 alone (P&amp;lt;0.05). In addition, the tumor size was further reduced by 25% in the group co-treated with EC-18 and cisplatin compared to the cisplatin alone (P&amp;lt;0.05), and it was observed that the tumor was disappeared in 3 mice in the co-treated group. In the positive control group, feed rate and body weight gradually decreased after about 12 days. Also, in the cisplatin-treated group, feed rate and body weight decreased rapidly after six days. On the other hand, in the group treated with EC-18 alone, there was no decrease in body weight and diet, and in the treatment with cisplatin, the diet and body weight gradually recovered after 14 days. Unlike the occurrence of oral mucositis symptoms independent of tumor growth inhibition by cisplatin, simultaneous treatment with EC-18 recovered oral mucositis symptoms along with the reduction of tumor growth (P&amp;lt;0.05). This effect could be explained by the fact that the expression of inflammation-related factors (TNFalpha, IL-1beta, IL-6) and DAMP (HMGB1, Adenosine) were effectively controlled by EC-18 (P&amp;lt;0.05). Conclusion: EC-18 can effectively inhibit the growth of HNSCC and alleviate the side effects caused by existing anticancer drugs at the same time. Therefore, it can be a desirable therapy for HNSCC patients. Citation Format: Guentae KIM, Eun Young Kim, Su-Hyun Shin, Hyowon Lee, Sun Young Yoon, Kaapjoo Park, Ki-young Sohn, Jae Wha Kim. EC-18 suppressed tumor growth and alleviated side effects caused by cisplatin in the HNSCC implantation model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5478.

Protective Effect of Silymarin and Gallic Acid against Cisplatin-Induced Nephrotoxicity and Hepatotoxicity.

Objective This study aimed to investigate the effects of gallic acid and silymarin against nephrotoxicity and hepatotoxicity caused by cisplatin. Materials and Methods In the study, 56 Wistar Albino rats were equally divided into eight groups. Group 1 was the control group; group 2 was the group receiving cisplatin; group 3 was the group receiving cisplatin + gallic acid; group 4 was the group receiving cisplatin + silymarin; group 5 was the group receiving cisplatin + silymarin + gallic acid; group 6 was the group receiving silymarin; group 7 was the group receiving gallic acid; group 8 was the group receiving gallic acid + silymarin. AST, ALT, urea, creatinine, albumin, globulin, and total protein levels were measured at the end of the study. Superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), glutathione (GSH), and 8-hydroxy-2′-deoxyguanosine (8OH-dG) levels were measured in kidney and liver tissues. Additionally, histopathological evaluations of the tissues were also performed. Results In kidney and liver tissues, cisplatin significantly increased MDA and 8-OHdG levels compared with treatment groups (p < 0.05). Silymarin-treated group significantly increased the SOD activity and GSH amount in the liver tissue compared with the cisplatin-treated group (p < 0.05). Gallic acid significantly increased CAT activity compared with the cisplatin-treated group (p < 0.05). It was determined that the cisplatin-treated group significantly decreased CAT and SOD activity compared with the control group (p > 0.05). Gallic acid showed a significant increase in CAT and SOD activity in kidney tissue compared with the cisplatin-treated group (p < 0.05). Conclusion As a result, it was observed that gallic acid silymarin had a protective effect on cisplatin-induced nephrotoxic and hepatotoxic effects.

Melatonin ameliorates cisplatin-induced neurodegeneration in medulla oblongata through the expressions of Aqp-1,-4, inflammation, and apoptosis pathway genes.

In this study, the neuroprotective effects of melatonin (MEL) with changes in apoptosis, inflammation, and histopathological morphology were evaluated in the medulla oblongata of cisplatin (CIS) administered rats. Although the side effects of CIS are known in many tissues, its reaction on the medulla oblongata and the molecular association underlying this effect is unclear. Male wistar albino rats were separated into four groups (control, CIS, CIS+MEL, and MEL) (n = 24). CIS and CIS+MEL groups were given 4 mg/kg CIS at 4-day intervals (days 1, 5, 9, and 13) by the first day of the study. The MEL and CIS+MEL groups were given 10 mg/kg MEL daily for 13 days. At the end of the study, the medulla oblongata sections of the rats were harvested on the 14th day, and the changes in gene expressions were examined. Expression levels of inflammation markers (TNF-α and IL-6), apoptotic markers (Bax and Casp-3), and Aqp-1 and Aqp-4 were found to significantly increase with CIS administration. On microscopic examination, hemorrhage, edema, and perivascular edema were detected in the CIS applied group compared with controls. MEL treatment significantly reduced perivascular edema (p = 0.0152) and hemorrhage (p = 0.0087). Besides, there was a significant difference between the control and CIS groups regarding pyknosis and a significant increase in pyknotic neurons in the CIS treatment group (p < 0.001). This study indicates that CIS treatment significantly impaired medulla oblongata, and combined treatment with MEL ameliorates the injury in rats.