CDDP Group Research Articles

Comparative Analysis of Epigallocatechin-3-Gallate and TNF-Alpha Inhibitors in Mitigating Cisplatin-Induced Pancreatic Damage Through Oxidative Stress and Apoptosis Pathways

Oxidative stress and inflammation caused by cisplatin, which is frequently used in the treatment of many cancers, damage healthy tissues as well as cancer cells. In this study, we aimed to investigate the effect of epigallocatechin-3-gallate (EGCG) and infliximab (INF) administration on pancreatic endocrine cells in rats treated with systemic cisplatin (CDDP). The rats were randomly divided into 6 groups: group 1 (control group), group 2 (EGCG group), group 3 (CDDP group), group 4 (EGCG + CDDP group), group 5 (CDDP + INF group), and group 6 (EGCG + CDDP + INF group). The study’s findings demonstrated that EGCG and INF effectively reduced the cellular damage induced by CDDP in histopathologic investigations of the pancreas. EGCG and INF, whether used individually or in combination, demonstrated a significant reduction in malondialdehyde (MDA) levels and an increase in glutathione (GSH) levels in the rat pancreas compared to the CDDP group. Immunohistochemically, the enhanced presence of insulin and glucagon positivity in the EGCG and INF groups, along with the absence of TUNEL immunopositivity, indicate that both treatments reduced CDDP-induced apoptosis. Furthermore, the observed lack of immunopositivity in TNF-α and 8-OHdG in the groups treated with EGCG and INF, compared to those treated with CDDP, indicates that these substances can inhibit inflammation. EGCG and INF, whether provided alone or together, can potentially reduce the damage caused to pancreatic islet cells by cisplatin. This effect is achieved through their anti-inflammatory and antioxidant properties during the early stages of the condition.

Lenvatinib plus hepatic arterial infusion chemotherapy with cisplatin for advanced hepatocellular carcinoma.

496 Background: A recent phase II study demonstrated that combination therapy with lenvatinib and hepatic arterial infusion chemotherapy using cisplatin (Lenva+CDDP) had high anti-tumor effects for patients with advanced hepatocellular carcinoma (HCC) with no prior history of systemic chemotherapy; however, whether the efficacy of Lenva+CDDP is superior to lenvatinib monotherapy remains unclear. Methods: We retrospectively reviewed the medical records of patients with advanced HCC and a Child–Pugh score of 5, 6, or 7 who were treated with Lenva+CDDP or lenvatinib, and compared the efficacy between the treatments. Patients in both groups received a once daily dose of lenvatinib (8 mg or 12 mg according to their weight), and the Lenva+CDDP group also received 65 mg/m2 of CDDP via the hepatic artery every 4 weeks. Treatment was repeated until tumor progression or unacceptable toxicity were observed. Results: A total of 140 patients (40 in the Lenva+CDDP group and 100 in the lenvatinib group) were included in this analysis. Patient backgrounds were comparable between the two groups, and 12 and 19 patients were previously treated with immunotherapy in the Lenva+CDDP group and lenvatinib group, respectively. The objective response rate and tumor control rate, assessed by RECIST ver1.1, in the Lenva+CDDP group were 67.5% and 100%, respectively, which was higher than in the lenvatinib group (17.0% and 87.0%, respectively). Median progression-free survival (PFS) and overall survival (OS) were 8.8 months and 19.6 months, respectively, in the Lenva+CDDP group, and 5.6 months and 20.3 months, respectively, in the lenvatinib group. Among patients who previously received immunotherapy, the median PFS, median OS, and 1-year survival rate were 9.7 months, not reached, and 87.5%, respectively, in the Lenva+CDDP group, and 4.7 months, 15.8 months, and 64.7%, respectively, in the lenvatinib group. Hematological toxicities were the main grade 3–4 adverse events (AEs) more frequently observed in the Lenva+CDDP group compared with the lenvatinib group. However, all grade 3–4 AEs were reversible, and there were no treatment-related deaths in either group. Conclusions: Lenva+CDDP demonstrated a better response and patient outcome than lenvatinib, and was well-tolerated in patients with advanced HCC. We are currently conducting a randomized controlled trial comparing the efficacy of these treatments.

Exploring the chondroitin sulfate nanogel's potential in combating nephrotoxicity induced by cisplatin and doxorubicin—An in-vivo study on rats

In this study, we aim to unveil the potential of itaconyl chondroitin sulfate nanogel (ICSNG) in tackling chronic kidney diseases triggered by the administration of CDDP and doxorubicin (Adriamycin, ADR). To that end, the new drug delivery system (ICSNG) was initially prepared, characterized, and loaded with the target drugs. Thereafter, the in-vivo studies were performed using five equally divided groups of 100 male Sprague-Dawley (SD) rats. Biochemical evaluation and immunohistochemistry studies have revealed the renal toxicity and the ameliorative effects of ICSNG on renal function. When ICSNG-based treatments were contrasted with the CDDP and ADR infected groups, they significantly increased paraoxonase-1 (PON-1), superoxide dismutase (SOD), catalase (CAT) and albumin activity and significantly decreased nitric oxide (NO), tumor necrosis factor alpha (TNF-α), creatinine, urea, and cyclooxygenase-2 (COX-2) activity (p < 0.001). The findings of the current study imply that ICSNG may be able to lessen renal inflammation and damage in chronic kidney disorders brought on by the administration of CDDP and ADR. Interestingly, according to the estimated selectivity indices, the ICSNG-encapsulated drugs have demonstrated superior selectivity for cancer MCF-7 cells, over healthy HSF cells, in comparison to the bare drugs.

Low-dose Cisplatin Induces Tumor Growth via Mobilization of Proangiogenic Bone Marrow-derived Cells in Mouse Models.

It is generally accepted that low-dose metronomic (LDM) chemotherapy mostly exerts its antitumor effects by inhibiting tumor angiogenesis. However, there is some evidence that LDM chemotherapy subsequently promotes tumor angiogenesis under certain regimens in animal models. The mechanisms responsible for these contradictory results are unclear. Cisplatin (CDDP) was intraperitoneally administered to tumor-bearing mice at doses of 0.05-3 mg/kg every other day. The effects of LDM chemotherapy with CDDP on tumor growth and angiogenesis were observed. To determine the involved mechanisms, we analyzed the expression of vascular basement membrane proteins, transcription of angiogenesis-related genes in tumor tissues, and mobilization of proangiogenic bone marrow-derived cells (BMDCs) in circulating blood. The mean tumor weight with the 3 mg/kg q.o.d. regimen CDDP was significantly lower (by 57.3%) in the CDDP than in the control group. However, the tumor weight was 52.1% higher for the 0.19 mg/kg q.o.d. regimen in the CDDP group, which could be antagonized using 30 mg/kg all-trans retinoic acid. For the 0.19 mg/kg q.o.d., more tumor vascular structures were observed in the CDDP than in the control group (47.9±5.0 vs. 22.3±0.8, p<0.001). The mobilization of VEGFR2+ BMDCs and the mRNA expression of the proangiogenic genes MMP9, VEGFR1, VEGFR2 and VE-cadherin were increased in the 0.19 mg/kg regimen. These results indicate that metronomic CDDP promoted tumor angiogenesis and tumor growth via increased mobilization of proangiogenic BMDCs at certain low doses. This implies a potential therapeutic risk from an inappropriate LDM chemotherapy dosage and suggests that optimizing the LDM chemotherapy regimen is urgently needed.

Therapeutic activity of green synthesized selenium nanoparticles from turmeric against cisplatin-induced oxido-inflammatory stress and cell death in mice kidney.

Cisplatin (CDDP) is a commonly prescribed chemotherapeutic agent; however, its associated nephrotoxicity limits its clinical efficacy and sometimes requires discontinuation of its use. The existing study was designed to explore the reno-therapeutic efficacy of turmeric (Tur) alone or conjugated with selenium nanoparticles (Tur-SeNPs) against CDDP-mediated renal impairment in mice and the mechanisms underlying this effect. Mice were orally treated with Tur extract (200 mg/kg) or Tur-SeNPs (0.5 mg/kg) for 7 days after administration of a single dose of CDDP (5 mg/kg, i.p.). N-acetyl cysteine NAC (100 mg/kg) was used as a standard antioxidant compound. The results revealed that Tur-SeNPs counteracted CDDP-mediated serious renal effects in treated mice. Compared with the controls, Tur or Tur-SeNPs therapy remarkably decreased the kidney index along with the serum levels of urea, creatinine, Kim-1, and NGAL of the CDDP-injected mice. Furthermore, Tur-SeNPs ameliorated the renal oxidant status of CDDP group demonstrated by decreased MDA and NO levels along with elevated levels of SOD, CAT, GPx, GR, GSH, and gene expression levels of HO-1. Noteworthy, lessening of renal inflammation was exerted by Tur-SeNPs via lessening of IL-6 and TNF-α besides down-regulation of NF-κB gene expression in mouse kidneys. Tur-SeNPs treatment also restored the renal histological features attained by CDDP challenge and hindered renal apoptosis through decreasing the Bax levels and increasing Bcl-2 levels. Altogether, these outcomes suggest that the administration of Tur conjugated with SeNPs is effective neoadjuvant chemotherapy to guard against the renal adverse effects that are associated with CDDP therapy.

STING-targeted PET tracer for early assessment of tumor immunogenicity in colorectal cancer after chemotherapy.

To optimize chemotherapy regimens and improve the effectiveness of chemotherapy combined with immunotherapy, a PET tracer specifically targeting the stimulator of interferon genes (STING), denoted as [18F]FBTA was used to monitor the early changes in tumor immunogenicity after chemotherapy in colorectal cancer (CRC) mice. The toluene sulfonate precursor was labeled with 18F to produce the STING targeted probe-[18F]FBTA. [18F]FBTA-PET imaging and biodistribution were performed using CRC mice treated with oxaliplatin (OXA) or cisplatin (CDDP). CRC mice were also treated with low (CDDP-LD: 1 mg/kg) or medium (CDDP-MD: 2.5 mg/kg) doses of CDDP, and subjected to PET imaging and biodistribution. The effects of different chemotherapeutic agents and different doses of CDDP on tumor innate immunity were verified by flow cytometry and immunohistochemistry. PET imaging of CRC mice exhibited notably enhanced tumor uptake in the early phase of chemotherapy with treatment with OXA (3.09 ± 0.25%ID/g) and CDDP (4.01 ± 0.18%ID/g), especially in the CDDP group. The PET-derived tumor uptake values have strong correlations with STING immunohistochemical score. Flow cytometry showed both agents led to DCs and macrophages infiltration in tumors. Compared with OXA, CDDP treatment recruits more DCs and macrophages in CRC tumors. Both CDDP-LD and CDDP-MD treatment elevated uptake in CRC tumors, especially in CDDP-MD group. Immunohistochemistry and flow cytometry confirmed CDDP-MD treatment recruits more DCs and macrophages than CDDP-LD treatment. Overall, the STING-targeted tracer-[18F]FBTA was demonstrated to monitor early changes in tumor immunogenicity in CRC mice after chemotherapy. Besides, the STING-targeted strategy may help to select the appropriate chemotherapy regimen, including chemotherapeutic agents and doses, which further improve clinical decision making for combination immunotherapy after chemotherapy for CRC.

Synergistic anticancer activity of cisplatin combined with tannic acid enhances apoptosis in lung cancer through the PERK-ATF4 pathway

BackgroundCisplatin (CDDP) is a common anticancer drug whose side effects limit its clinical applications. Tannins (TA) are plant-derived polyphenols that inhibit tumor growth in different types of cancer. Here, we evaluated the anticancer effect of TA combined with CDDP on lung cancer cell lines (GLC-82 and H1299) and investigated the underlying molecular mechanism of endoplasmic reticulum (ER) stress-induced apoptosis.MethodsCell lines were treated with CDDP, TA, and CDDP + TA, and the effect of the combination was assessed using MTT assay and observed under light and fluorescence microscopes. Cell apoptosis was detected by flow cytometry, and the levels of ERS apoptosis pathway related genes were valuated by qRT-PCR and western blotting. The effects of the drug combination on the tumors of nude mice injected with H1299 cells were investigated, and the expression of key factors in the ER stress apoptotic pathway was investigated.ResultsThe combination of CDDP and TA significantly inhibited lung cancer cell viability indicating a synergistic antitumoral effect. The mRNA and protein expression levels of key ER stress factors in the CDDP + TA group were considerably higher than those in the CDDP and TA groups, the tumor volume in tumor-bearing mice was the smallest, and the number of apoptotic cells and the protein expression levels of the key ER stress in the combination group were considerably higher.ConclusionsThe combination of TA and CDDP may produce synergistic antitumoral effects mediated by the PERK-ATF4-CHOP apoptotic axis, suggesting a novel adjuvant treatment for lung cancer.

The combination of quercetin and leucine synergistically improves grip strength by attenuating muscle atrophy by multiple mechanisms in mice exposed to cisplatin.

Both quercetin and leucine have been shown to exert moderately beneficial effects in preventing muscle atrophy induced by cancers or chemotherapy. However, the combined effects of quercetin and leucine, as well as the possible underlying mechanisms against cisplatin (CDDP)-induced muscle atrophy and cancer-related fatigue (CRF) remain unclear. To investigate the issues, male BALB/c mice were randomly assigned to the following groups for 9 weeks: Control, CDDP (3 mg/kg/week), CDDP+Q (quercetin 200 mg/kg/day administrated by gavage), CDDP+LL (a diet containing 0.8% leucine), CDDP+Q+LL, CDDP+HL (a diet containing 1.6% leucine), and CDDP+Q+HL. The results showed that quercetin in combination with LL or HL synergistically or additively attenuated CDDP-induced decreases in maximum grip strength, fat and muscle mass, muscle fiber size and MyHC level in muscle tissues. However, the combined effects on locomotor activity were less than additive. The combined treatments decreased the activation of the Akt/FoxO1/atrogin-1/MuRF1 signaling pathway (associated with muscle protein degradation), increased the activation of the mTOR and E2F-1 signaling pathways (associated with muscle protein synthesis and cell cycle/growth, respectively). The combined effects on signaling molecules present in muscle tissues were only additive or less. In addition, only Q+HL significantly increased glycogen levels compared to the CDDP group, while the combined treatments considerably decreased CDDP-induced proinflammatory cytokine and MCP-1 levels in the triceps muscle. Using tumor-bearing mice, we demonstrated that the combined treatments did not decrease the anticancer effect of CDDP. In conclusion, this study suggests that the combination of quercetin and leucine enhanced the suppressed effects on CDDP-induced muscle weakness and CRF through downregulating muscle atrophy and upregulating the glycogen level in muscle tissues without compromising the anticancer effect of CDDP. Multiple mechanisms, including regulation of several signaling pathways and decrease in proinflammatory mediator levels in muscles may contributed to the enhanced protective effect of the combined treatments on muscle atrophy.

The ameliorative effect of Primula vulgaris on cisplatin-induced nephrotoxicity in rats and quantification of its phenolic components using LC-ESI-MS/MS

Cisplatin (CDDP) is an important chemotherapeutic agent, accumulation of which in kidney tissue causes nephrotoxicity and renal failure. The aim of this study was to evaluate, for the first time in the literature, the protective effect of dimethyl sulfoxide (DMSO) extract of Primula vulgaris leaf (PVE) against CDDP-induced nephrotoxicity in rats.The PVE content was characterized using liquid chromatography-mass spectrometry. Nephrotoxicity was induced with a single dose of CDDP (7.5 mg/kg). Thirty female Wistar-Albino rats were divided into five groups (control, DMSO, CDDP (7.5 mg/kg), CDDP + PVE (25 mg/kg), and CDDP + PVE (50 mg/kg)). Biochemical and histopathological analyses were then performed.Rutin, gallic acid, p-coumaric acid and protocatechuic acid were identified as major components of PVE. Total antioxidant status and glutathione (GSH) values increased significantly in the serum samples from the treatment group compared to the CDDP group, while blood urea nitrogen, creatinine, oxidative stress index, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), total oxidant status, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) values decreased significantly. GSH levels increased significantly in the treatment group compared to the CDDP group, while TNF-α, caspase-3, 8-OHdG, MDA levels and damage scores decreased significantly.In conclusion, PVE exhibited strong protective effects through its anti-apoptotic, antioxidant, and anti-inflammatory activities against nephrotoxicity and oxidative damage caused by CDDP in rats.

Abstract 3779: Evaluation of anti-cancer efficacy of lipid nanoparticles containing siRNA against HPV16 E6 and E7 combined with cisplatin in xenograft model of cervical cancer

Abstract Background: High-risk human papillomavirus (HPV) type 16 is the major etiological agent found in more than 60% of patients with cervical cancer and associated with cancer development and progression. Persistent expression HPV E6 and E7 oncoproteins are essential for the initiation and maintenance of cervical cancer. The therapeutic approaches targeting HPV E6 and E7 have been proved to be highly efficient in killing malignant cells. The suppression of HPV 16 E6/E7 expression by the short interfering RNA (siRNA) was more effective in combination therapy with cisplatin (CDDP) for cervical cancer. ENB101-LNP is an ionizable lipid nanoparticles (LNPs) encapsulating siRNA against E6/E7 of HPV 16 for delivery to the tumor cells. Methods: To investigate the anticancer efficacy and mechanism of ENB101-LNP combined with cisplatin in cervical cancer; the xenograft model was generated by the injection of CaSki cells subcutaneously into BALB/c nude mice. Mice were randomly divided into six groups: 1) blank control; 2) 1mg/kg ENB101-LNP; 3) 3mg/kg ENB101-LNP; 4) CDDP; 5) 1mg/kg ENB101-LNP-CDDP; 6) 3mg/kg ENB101-LNP-CDDP. ENB101-LNP was treated with intravenous injection three times weekly for 3 weeks and CDDP was treated with IP injection once a week for 3 weeks. Tumor growth curves were plotted to calculate the tumor inhibition rate. Mice were sacrificed one week after the last treatment and the tumor tissues were investigated using histopathology, immunohistochemical staining and western blotting. Results: Compared with the control and the other treatment groups, the tumor growth was significantly inhibited (P &amp;lt; 0.05). The tumor inhibition rate was 29.7% in 1mg/kg ENB101-LNP group, 29.6% in 3mg/kg ENB101-LNP group, 34.0% in CDDP group, 47.0% in 1mg/kg ENB101-LNP-CDDP group. At the dose of 3mg ENB101-LNP/kg combined with CDDP exhibited superior antitumor efficacy, the tumor inhibition rate was 68.8%. The successful ENB101-LNP mediated knockdown (with up to 80%) of HPV16 E6/E7 in tumors of both 1mg/kg and 3mg/kg groups was confirmed by RT-PCR. The ENB101-LNP increased p53 and p21 expression in tumors compared to control and CDDP alone groups and combination treatment with CDDP showed decreased expression of PD-L1 expression compared to CDDP alone group. The treatment of ENB101-LNP and combination with CDDP showed significant increase in apoptotic cells compared to control and single-agent groups respectively. Conclusions: The ENB101-LNP inhibiting E6 and E7 of HPV 16 in combination with CDDP showed promising anticancer activity in the cervical cancer cells xenograft mouse model. Citation Format: Sung Wan Kang, Shin-Wha Lee, Ji-young Lee, Ok Ju Kang, Hyejeong Kim, Yisak Kim, Yong-Man Kim. Evaluation of anti-cancer efficacy of lipid nanoparticles containing siRNA against HPV16 E6 and E7 combined with cisplatin in xenograft model of cervical cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3779.

Mechanism of ferroptosis in a rat model of premature ovarian insufficiency induced by cisplatin

Ferroptosis is widely present in fibrosis-related diseases. The basic pathology of premature ovarian insufficiency (POI) involves ovarian tissue fibrosis, and there are currently fewer relevant studies addressing the association between ferroptosis and POI. This study aimed to demonstrate that ferroptosis induced by cisplatin (CDDP) caused ovarian tissue fibrosis, leading to POI. Vitamin E (VE), a ferroptosis inhibitor, could repair damaged ovarian function. CDDP was used to establish a rat model of POI, and VE was administered to reverse the reproductive toxicity of CDDP. Ovarian function was assessed by histological section staining, follicle counts, sex hormone levels, as well as fertility assays. The extent of ferroptosis was assessed by transmission electron microscopy (TEM), malondialdehyde (MDA), Perls staining. CCK-8, Ethynyl-2-Deoxyuridine (EdU), and scratch assays were used to determine the effect of CDDP and VE on ovarian granulosa cell (GC) viability. Western blot, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were performed to evaluate ferroptosis-related molecular changes. Our results showed that CDDP caused follicle development disorders and ovarian tissue fibrosis, the levels of sex hormones suggested impaired ovarian function, and VE could reverse the reproductive toxicity of CDDP. The results of TEM, MDA and Perls staining suggested that the typical mitochondrial signature of ferroptosis was altered in ovarian GCs from the CDDP group, with significantly higher levels of lipid peroxidation and significant iron deposition in ovarian tissue, whereas VE mitigated the extent of ferroptosis. Molecular experiments then confirmed that the ferroptosis-related molecules acetyl CoA synthetase long chain family member 4 (ACSl4), 15-lipoxygenase-1 (ALOX15), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) were differentially expressed in each group. In summary, our study preliminarily demonstrated that CDDP may promote GCs to undergo ferroptosis, cause follicle development disorders, ovarian tissue fibrosis, and induce POI by regulating the expression of ACSl4, ALOX15, SLC7A11, and GPX4, while VE improved impaired ovarian function.

Study on the effect of 5-aminolevulinic acid-mediated photodynamic therapy combined with cisplatin on human ovarian cancer OVCAR-3 ​cells

PurposeThis article explores the effect of 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy (PDT) combined with cisplatin (CDDP) on the apoptosis of human ovarian cancer cells and the mechanism of action of the combination therapy. Materials and methodsHuman ovarian cancer OVCAR-3 ​cells were cultured in vitro and divided into 5-ALA/PDT group, CDDP group and combined treatment group (5-ALA/PDT combined with different concentrations of CDDP). After administration of the corresponding drugs, a CCK-8 assay was used to detect the inhibition rate of cell proliferation. After Rhodamine 123 staining, mitochondrial membrane potential changes were observed under fluorescence microscopy. The apoptosis rate and reactive oxygen species (ROS) content were detected by flow cytometry. Western blotting was used to detect protein expression. ResultsThe CCK-8 assay showed that CDDP in combination with 5-ALA/PDT significantly enhanced cytotoxicity compared to treatment with CDDP alone and that low doses of CDDP were sufficient to induce these combination effects. The mitochondrial membrane potential in each combination treatment group gradually decreased with increasing CDDP concentration, while the apoptosis rate and reactive oxygen species (ROS) content detected by flow cytometry gradually increased. Western blotting assay showed that the expression of bax, cleaved caspase-9, cleaved caspase-3, and cleaved PARP was increased, while the expression of bcl-2, caspase-9, caspase-3, and PARP was decreased, and the differences were statistically significant (P ​< ​0.05). ConclusionsIn summary, 5-ALA/PDT combined with CDDP can effectively inhibit cell proliferation and promote apoptosis, and this combination may induce apoptosis by activating the mitochondrial pathway.

Cisplatin causes erectile dysfunction by decreasing endothelial and smooth muscle content and inducing cavernosal nerve senescence in rats.

Cisplatin (cis-diamminedichloroplatinum II, CDDP), a drug widely used for cancer worldwide, may affect erectile function, but its side effects have not received enough attention. To investigate the effect of CDDP on erectile function and its possible mechanism. Sprague-Dawley rats were intraperitoneally administered CDDP (CDDP group) or the same volume of normal saline (control group). Erectile function was evaluated after a one-week washout. Then, histologic changes in the corpus cavernosum and cavernous nerve (CN) were measured. Other Sprague-Dawley rats were used to isolate the major pelvic ganglion and cavernous nerve (MPG/CN). RSC96 cells were then treated with CDDP. SA-β-gal staining was used to identify senescent cells, and qPCR was used to detect the senescence-associated secretory phenotype (SASP). Finally, the supernatant of RSC96 cells was used to culture MPG/CN. Erectile function was measured after administration of CDDP. The cavernosum levels of α-SMA, CD31, eNOS, and γ-H2AX, the apoptosis rate and the expression of p16, p21 and p53 in CN were also assayed. The senescent phenotype of RSC96 cells treated with CDDP was identified, and neurite growth from the MPG/CN was photographed and measured. The CDDP group had a significantly lower ICP/MAP ratio than the control group. Compared to the control group, the CDDP group exhibited significantly lower α-SMA, CD31 and eNOS levels and significantly higher γ-H2AX and apoptosis rates in corpus cavernosum. In addition, CDDP increased some senescence markers p16, p21 and p53 in CN. In vitro, CDDP induced RSC96 senescence and SASP, and the supernatant of senescent cells slowed neurite outgrowth of MPG/CN. CDDP treatment could induce erectile dysfunction, by affecting the content of endothelial and smooth muscle and causing SASP in CN. The results indicate that CDDP treatment should be considered as a risk factor for ED. Clinicians should pay more attention to the erectile function of cancer patients who receive CDDP treatment.

The diminution and modulation role of water-soluble gallic acid-carboxymethyl chitosan conjugates against the induced nephrotoxicity with cisplatin

The toxicity of cisplatin (CDDP) toward the renal tubules and its severe effects on the proximal tubules limits its further use in cancer therapy. The current study was undertaken to evaluate the protective effects of gallic acid-grafted O-carboxymethyl chitosan (GA@CMCS) against nephrotoxicity induced by CDDP in rats. Renal injury was assessed in the GA@CMCS/CDDP-treated rats using kidney injury molecule-1 (KIM-1). Moreover, the levels of reduced glutathione (GSH), malondialdehyde (MDA), and nitric oxide (NO) were measured. The comet assay was performed to measure the DNA damage. The renoprotective activity of GA@CMCS was supported by histo- and immuno-pathological studies of the kidney. GA@CMCS significantly normalized the increases in kidney homogenate of KIM-1, MDA, and NO-induced by CDDP and significantly increased GSH as compared with the CDDP group. GA@CMCS also significantly protects rat kidneys from CDDP-induced histo- and immuno-pathological changes. Both biochemical findings and histo- and immuno-pathological evidence showed the renoprotective potential of GA@CMCS against CDDP-induced oxidative stress, inflammation, and renal dysfunction in rats. In conclusion, GA@CMCS has been shown to mitigate the nephrotoxicity impact of CDDP in cancer therapy.

Untargeted metabolomics analysis of omeprazole-enhanced chemosensitivity to cisplatin in mice with non-small cell lung cancer

Drug resistance of tumors remains a major barrier in cisplatin (CDDP)-based chemotherapy. Omeprazole (OME) is often utilized during chemotherapy to alleviate gastrointestinal symptoms. In a previous investigation, we demonstrated a protective effect of OME against CDDP-induced kidney injury. To further establish whether OME could enhance chemosensitivity to CDDP and the underlying mechanisms, an in vivo tumor-bearing mouse model with CDDP-resistant A549 non-small cell lung cancer (A549/CDDP) was established in the current study. A high-performance liquid chromatography-time of flight mass spectrometry (HPLC-TOF/MS)-based untargeted metabolomics approach for tumor tissue and serum was employed to explore the mechanisms underlying the enhanced therapeutic effects of co-administration of CDDP and OME. Notably, tumor weights of mice in the CDDP + OME group were significantly decreased compared with those treated with CDDP alone. HE and TUNEL staining revealed more significant apoptosis of tumor cells in the group co-administered CDDP + OME relative to CDDP alone. Overexpression of multidrug resistance-associated protein 2 in CDDP-resistant tumors was significantly reversed upon treatment with CDDP + OME. PCA score plots of the groups co-treated with CDDP + OME were clearly separated from those treated with CDDP alone in metabolomics analysis for tumor and serum samples, clearly suggesting that co-administration of OME enhances the antitumor effect of CDDP. Subsequently, 10 and 7 metabolites in CDDP + OME group with significant changes in tumor and serum compared with CDDP group, respectively, were identified. Pathway analysis both in tumor and serum samples revealed regulation of the metabolism of purines, several amino acids and riboflavin in enhanced chemotherapy with both OME and CDDP. The collective findings provide beneficial novel insights into drug-drug interactions, which could improve the application of CDDP in clinical practice.

Delivery of cisplatin and resiquimod in nanomicelles for the chemoimmunotherapy of ovarian cancer

BackgroundTo explore the effect and mechanism of delivery of cisplatin (CDDP) and resiquimod in nanomicelles for the chemoimmunotherapy of ovarian cancer in vivo and in vitro.MethodsPoly(l-glutamic acid)-graft-methoxypolyethylene glycols (PLG-g-mPEG) was used to carry cisplatin and resiquimod for the preparation of CDDP/resiquimod/PLG-g-mPEG. We determined the loading content (LC) and encapsulation efficiency (EE), and then observed the particle shape, particle size distribution and zeta potential. In this study, we recruited 30 healthy adult participants and isolated mononuclear cells, and they were randomly classified into a control group, a CDDP group, a resiquimod group, a CDDP/resiquimod/PLG-g-mPEG group and a IFN-γ + LPS group to identify macrophages markers in different polarization states. We conducted microprobe synchrotron radiation X-ray fluorescence (SRXRF) imaging to observe the cell uptake. Furthermore, we observed the effects of CDDP/resiquimod/PLG-g-mPEG on the growth and colony formation of SW626 cells and the expressions of apoptosis-associated genes and proteins. Tumor-bearing mouse models of ovarian cancer were prepared and randomized into a negative control group, a PLG-g-mPEG group, a CDDP group, a resiquimod group and a CDDP/resiquimod/PLG-g-mPEG group, so as to analyze the anti-cancer effect of CDDP/resiquimod/PLG-g-mPEG in vivo.ResultsThe LC and EE of CDDP/resiquimod/PLG-g-mPEG were 19.42% and 90.12%, respectively. Nanoparticles were uniform spherical in shape and closely arranged together, with a typical core–shell structure, and their average particle size and zeta potential were 82.36 nm and − 23.69 mV, respectively. When CDDP/resiquimod/PLG-g-mPEG group was compared with the control group, the positive expression rate of CD16 in the CDDP/resiquimod/PLG-g-mPEG group highly increased, whereas the positive expression rate of CD163 dramatically decreased. In the meantime, Arg1 and Mrc1 mRNA expressions significantly decreased whereas IL-12 and NOS2 mRNA expressions dramatically increased (P < 0.05). Elemental mapping of cells exhibited notable internalization of cisplatin delivered by CDDP/resiquimod/PLG-g-mPEG to cytoplasm. We compared the cell survival rate between the CDDP/resiquimod/PLG-g-mPEG group and the control group, the CDDP/resiquimod/PLG-g-mPEG group sharply reduced (P < 0.05). What’s more, the inhibitory effect got strengthened as the reaction time was prolonged, with the synergy coefficient of 0.31.ConclusionPLG-g-mPEG-loaded CDDP and resiquimod effectively achieves the targeted delivery of chemotherapy and immunotherapy, with a strong synergistic anti-cancer effect.

Protective effects of tadalafil against cisplatin-induced spermatogenic dysfunction

BackgroundCisplatin (CDDP) is an effective anticancer drug for the treatment of malignant tumors, such as lung cancer, bladder cancer, and testicular cancer. However, oligozoospermia and azoospermia after administration of CDDP are clinical problems. One of the testicular toxicities of CDDP is known to cause oxidative stress. Tadalafil has been reported to exhibit antioxidant effects and is widely used in clinical practice to treat benign prostatic hyperplasia and erectile dysfunction. Rho-kinase α (ROCK2) regulates cell migration and apoptosis and has been reported to be involved in CDDP-induced nephrotoxicity. The excessive expression of ROCK2 is known to cause oxidative stress. ObjectiveThe objective of the current study was to test the effect of tadalafil on the testicular toxicity of CDDP. Material and methodsThirty-two rats were used and divided into the following four groups. (1) The control group (CONT), treated with saline on day 1 and saline and dimethyl sulfoxide (DMSO) on days 1–10 intraperitoneally (i.p.) (2) The Tadalafil Group (TAD), treated with saline on day 1, and 0.4 mg/kg tadalafil on days 1–10 i.p. (3) The CDDP group (CD), treated with 7 mg/kg CDDP, saline, and DMSO on days 1–10 i.p. and (4) The CDDP + TAD group (CDT) was treated with 7 mg/kg CDDP on day 1, and 0.4 mg/kg tadalafil on days 1–10 i.p. Testes and epididymides samples were collected on day 11. Biochemical and pathological analyses and quantitative polymerase chain reaction were performed on the excised specimens. ResultsCDDP treatment resulted in testicular atrophy, decreased sperm concentration, and atrophy of seminiferous tubules as observed from the testicular histology. Increased apoptosis of seminiferous tubules, oxidative stress, and ROCK2 mRNA expression were observed after CDDP treatment. Treatment with tadalafil improved these adverse effects. ConclusionTadalafil is a potential drug for reducing CDDP-induced spermatogenic dysfunction. The antioxidant effect of tadalafil may be partly responsible for this phenomenon. ROCK2 and oxidative stress markers may be involved in the possible antioxidant effects of tadalafil. Tadalafil may be considered as one of a treatment option for reducing spermatogenic dysfunction after administration of CDDP.

Evaluation of the Effect of Mesenchymal Stem Cells on Cisplatin Induced Toxicity in Neuroblastoma Tumor Model

Objective: High-dose cisplatin (CDDP) causes dose-limiting side effects in neuroblastoma (NB) treatment. Mesenchymal stem cells (MSC) are a current research area. The aim of this study is to assess the interaction of MSC with CDDP in nude mouse NB model. Methods: Athymic male nude mice (n=28) thatbhad basal auditory tests, with subcutaneous NB were randomized to control, CDDP, MSC and CDDP+MSC treatment groups. Seven days later, hearing tests were repeatedand the animals were sacrificed. Necrosis, apoptosis and viabilitywere assessed in tumors. MSC rate within the tumor was assessed with flow cytometry for triple CD34+ CD44+ and CD117- expression. Expression of the cochlear cell proteins of calretinin, math-1 and myosin2A were immunohistochemically assessed. Results: Tumor tissues were found to have statistically significantly higher levels of necrosis in CDDP and CDDP+MSC groups. MSC did not change the tumor dimensions in the CDDP group. MSC group had higher triple CD34+ CD44+ and CD117- expression within tumor tissue compared to the control and CDDP groups. In the inner ear, the expression of cochlear cell proteins calretinin, math-1 and myosin2A were identified to be highest in MSC group. 15-decibel loss at 12, 16, 20 and 32 kHz frequencies with CDDP was resolved with MSC administration. Conclusion: MSC prevented hearing loss caused by CDDP without disrupting the antitumor effect of CDDP. Systemic MSC may be assessed for clinical use to reduce the side effects of CDDP.

Ameliorative effect of gallic acid on cisplatin-induced ovarian toxicity in rats

The aim of the present study was to evaluate the protective effect of gallic acid (GA) against cisplatin (CDDP)-induced ovarian toxicity, for the first time. The ovarian damage was generated with CDDP (5 mg/kg) intraperitoneally (i.p.) administration in rats. GA (2.5 and 5 mg/kg) were administered i.p. for 3 consecutive days. The study was carried out in 5 main groups containing 6 rats in each group: control, GA (5 mg/kg), CDDP, CDDP + GA (2.5 mg/kg) and CDDP + GA (5 mg/kg). The levels of ovarian malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), catalase (CAT), 8-hydroxy-2'-deoxyguanosine (8-OHdG), caspase-3 and tumor necrosis factor-alpha (TNF-α) were determined. Hematoxylin and eosin staining method was employed for the histopathological examination. In the CDDP group, it is determined that statistically significant decreasing in the levels of TAS and CAT, and increasing in the levels of MDA, TOS, OSI, 8-OHdG, caspase-3 and TNF-α (p < 0.05) compared with control group. GA administrations statistically significantly restored this damage (p < 0.05). Although vascular congestion, edema, hemorrhage, follicular degeneration and leukocyte infiltration were significantly higher in the CDDP group than in the control group, GA administrations statistically significantly restored these damages (p < 0.05). In conclusion, this study showed that GA prevented CDDP-induced ovarian damage with its antioxidant, anti-apoptotic and anti-inflammatory activities. More comprehensive studies are needed to see the underlying mechanisms.

P-Coumaric acid alleviates cisplatin-induced ovarian toxicity in rats.

The therapeutic value of cisplatin (CDDP) as an anticancer drug is limited by its ovo-otoxicity. The effect of natural phenolic acids in the prevention of many diseases related to oxidative stress has been reported. Here, the ability of p-coumaric (pCA) acid, a member of phenolic acids, to protect rat ovary tissue against CDDP-induced oxidative stress was investigated. The study was carried out in five main groups containing six rats in each group: control, pCA (4mg/kg), CDDP, CDDP plus pCA (2mg/kg), and CDDP plus pCA (4mg/kg). The levels of ovarian malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), catalase (CAT), 8-hydroxy-2'-deoxyguanosine (8-OHdG), caspase-3, and tumor necrosis factor-alpha (TNF-α) were determined. Hematoxylin and eosin staining method was employed for the histopathological examination. In the CDDP group, it is determined that statistically significant decreasing in the levels of TAS and CAT, and increasing in the levels of MDA, TOS, OSI, 8-OHdG, caspase-3, and TNF-α compared with control group (p < 0.05). pCA administration statistically significantly restored this damage in a dose-dependent manner (p < 0.05). Although vascular congestion, edema, hemorrhage, follicular degeneration, and leukocyte infiltration were significantly higher in the CDDP group than in the control group, pCA administrations statistically significantly restored these damages (p < 0.05). The data presented here indicate that pCA protects ovarian tissues of rats against CDDP-induced oxidative stress, inflammation, and apoptosis. It may be worthy to consider the usefulness of pCA as adjuvant therapy in cancer management.