PD-1 Inhibition Minimally Affects Cisplatin-Induced Toxicities in a Murine Model.
Ontology highlight
ABSTRACT:
SUBMITTER: Spielbauer K
PROVIDER: S-EPMC6134261 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
Publications
PD-1 Inhibition Minimally Affects Cisplatin-Induced Toxicities in a Murine Model.
Spielbauer Katie K Cunningham Lisa L Schmitt Nicole N
Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery 20180403 2
Immune checkpoint inhibition used in combination with standard cisplatin-based chemotherapy regimens is currently under evaluation in clinical trials for head and neck squamous cell carcinoma (HNSCC). The impact of anti-PD-1 therapy on cisplatin-induced ototoxicity and nephrotoxicity has not been established. Here we use a murine model of cisplatin-induced hearing loss to investigate the impact of anti-PD-1 immunotherapy on auditory brainstem responses (ABRs), distortion product otoacoustic emis ...[more]
Similar Datasets
Project description:Most patients with muscle-invasive bladder cancer (MIBC) are not cured with platinum chemotherapy. Up-regulation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF-κB signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF-κB signaling and patient survival. The efficacy of cisplatin plus the NF-κB inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. Platinum-naive claudin-low MIBC showed constitutive NF-κB signaling and this was associated with reduced disease-specific survival in TCGA patients. Chemotherapy up-regulated NF-κB signaling and chemoresistance-associated genes, including SPHK1, PLAUR, and SERPINE1. In mice, DMAPT significantly improved the efficacy of cisplatin in both models. The combination preserved body weight, renal function, and morphology, reduced muscle fatigue and IL-6 serum levels, and did not aggravate immuno-hematological toxicity compared with cisplatin alone. These data provide a rationale for combining NF-κB inhibition with platinum-based chemotherapy and conducting a clinical trial in MIBC patients.
| S-EPMC10701775 | biostudies-literature
Project description:BackgroundCisplatin is an effective anticancer drug that elicits many side effects mainly due to induction of oxidative and nitrosative stresses during prolonged chemotherapy. The severity of these side effects consequently restricts its clinical use under long term treatment. Riboflavin is an essential vitamin used in various metabolic redox reactions in the form of flavin adenine dinucleotide and flavin mononucleotide. Besides, it has excellent photosensitizing property that can be used to ameliorate these toxicities in mice under photodynamic therapy.Methods and findingsRiboflavin, cisplatin and their combinations were given to the separate groups of mice under photoilluminated condition under specific treatment regime. Their kidney and liver were excised for comet assay and histopathological studies. Furthermore, Fourier Transform Infrared Spectroscopy of riboflavin-cisplatin combination in vitro was also conducted to investigate any possible interaction between the two compounds. Their comet assay and histopathological examination revealed that riboflavin in combination with cisplatin was able to protect the tissues from cisplatin induced toxicities and damages. Moreover, Fourier Transform Infrared Spectroscopy analysis of the combination indicated a strong molecular interaction among their constituent groups that may be assigned for the protective effect of the combination in the treated animals.ConclusionInclusion of riboflavin diminishes cisplatin induced toxicities which may possibly make the cisplatin-riboflavin combination, an effective treatment strategy under chemoradiotherapy in pronouncing its antineoplastic activity and sensitivity towards the cancer cells as compared to cisplatin alone.
| S-EPMC3342168 | biostudies-literature
Project description:Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence.
| S-EPMC6377815 | biostudies-literature
Project description:Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [(3)H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [(3)H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.
| S-EPMC4268146 | biostudies-literature
Project description:PurposeCarnitine is an essential cofactor for mitochondrial fatty acid oxidation that is actively reabsorbed by the luminal transporter Octn2 (Slc22a5). Because the nephrotoxic agent cisplatin causes urinary loss of carnitine in humans, we hypothesized that cisplatin may affect Octn2 function.Experimental designExcretion of carnitine and acetylcarnitine was measured in urine collected from mice with or without cisplatin administration. The transport of carnitine was assessed in cells that were transfected with OCT1 or OCT2. The effect of cisplatin treatment on gene expression was analyzed using a mouse GeneChip array and validated using quantitative reverse transcriptase-PCR.ResultsIn wild-type mice, urinary carnitine excretion at baseline was ∼3-fold higher than in mice lacking the basolateral cisplatin transporters Oct1 and Oct2 [Oct1/2(-/-) mice], indicating that carnitine itself undergoes basolateral uptake into the kidney. Transport of carnitine by OCT2, but not OCT1, was confirmed in transfected cells. We also found that cisplatin caused an increase in the urinary excretion of carnitine and acetylcarnitine in wild-type mice but not in Oct1/2(-/-) mice, suggesting that tubular transport of cisplatin is a prerequisite for this phenomenon. Cisplatin did not directly inhibit the transport of carnitine by Octn2 but downregulated multiple target genes of the transcription factor peroxisome proliferator activated receptor α, including Slc22a5, in the kidney of wild-type mice that were absent in Oct1/2(-/-) mice.ConclusionOur study shows a pivotal role of Oct1 and Oct2 in cisplatin-related disturbances in carnitine homeostasis. We postulate that this phenomenon is triggered by deactivation of peroxisome proliferator activated receptor α and leads to deregulation of carnitine-shuttle genes.
| S-EPMC3531239 | biostudies-literature
Project description:Cisplatin is a chemotherapeutic agent widely used in the treatment of various cancers, but its application is often limited due to complications such as acute kidney injury (AKI). Orexins are hypothalamic neuropeptides that modulate the sleep-wake cycle, neuroendocrine function, and the autonomic nervous system. Emerging evidence suggests that orexin A (OXA) has anti-inflammatory and neuroprotective effects in animal models of neuroinflammatory diseases of the central nervous system. However, the effect of OXA on kidney diseases has not been examined. Here, we investigated whether OXA has a protective effect in a murine model of cisplatin-induced AKI. Intraperitoneal administration of OXA ameliorated renal dysfunction, and histological abnormalities in mice injected with cisplatin. OXA inhibited cisplatin-induced oxidative stress through the modulation of prooxidant and antioxidant enzymes. This peptide reduced apoptotic cell death by inhibiting the p53-mediated pathway in mice injected with cisplatin. OXA also alleviated cisplatin-induced cytokine production and macrophage infiltration into injured kidneys. Taken together, these results showed that OXA ameliorates cisplatin-induced AKI via antioxidant, anti-apoptotic, and anti-inflammatory actions. This peptide could be a potential therapeutic agent for cisplatin-induced AKI.
| S-EPMC9740499 | biostudies-literature
Project description:Sequencing data from different types of cancers including melanomas demonstrate that tumors with high mutational loads are more likely to respond to immune checkpoint blockade (ICB) therapies. We have previously shown that low-dose intratumoral injection of the chemotherapeutic DNA damaging drug cisplatin activates intrinsic mutagenic DNA damage tolerance pathway, and when combined with ICB regimen leads to tumor regression in the mouse YUMM1.7 melanoma model. We now report that tumors generated with an in vitro cisplatin-mutagenized YUMM1.7 clone (YUMM1.7-CM) regress in response to ICB, while an identical ICB regimen alone fails to suppress growth of tumors generated with the parental YUMM1.7 cells. Regressing YUMM1.7-CM tumors show greater infiltration of CD8 T lymphocytes, higher granzyme B expression, and higher tumoral cell death. Similarly, ex-vivo, immune cells isolated from YUMM1.7-CM tumors-draining lymph nodes (TDLNs) co-incubated with cultured YUMM1.7-CM cells, eliminate the tumor cells more efficiently than immune cells isolated from TDLNs of YUMM1.7 tumor-bearing mice. Collectively, our findings show that in vitro induced cisplatin mutations potentiate the antitumor immune response and ICB efficacy, akin to tumor regression achieved in the parental YUMM1.7 model by ICB administered in conjunction with intratumoral cisplatin injection. Hence, our data uphold the role of tumoral mutation burden in improving immune surveillance and response to ICB, suggesting a path for expanding the range of patients benefiting from ICB therapy.
| S-EPMC8290318 | biostudies-literature
Project description:Optic atrophy1 (OPA1) is crucial for inner mitochondrial membrane (IMM) fusion and essential for maintaining crista structure and mitochondrial morphology. Optic atrophy and hearing impairment are the most prevalent clinical features associated with mutations in the OPA1 gene, but the function of OPA1 in hearing is still unknown. In this study, we examined the ability of Opa1 to protect against cisplatin-induced cochlear cell death in vitro and in vivo. Our results revealed that knockdown of Opa1 affects mitochondrial function in HEI-OC1 and Neuro 2a cells, as evidenced by an elevated reactive oxygen species (ROS) level and reduced mitochondrial membrane potential. The dysfunctional mitochondria release cytochrome c, which triggers apoptosis. Opa1 expression was found to be significantly reduced after cell exposed to cisplatin in HEI-OC1 and Neuro 2a cells. Loss of Opa1 aggravated the apoptosis and mitochondrial dysfunction induced by cisplatin treatment, whereas overexpression of Opa1 alleviated cisplatin-induced cochlear cell death in vitro and in explant. Our results demonstrate that overexpression of Opa1 prevented cisplatin-induced ototoxicity, suggesting that Opa1 may play a vital role in ototoxicity and/or mitochondria-associated cochlear damage.
| S-EPMC8490775 | biostudies-literature
Project description:Simple Summary This experimental study was designed in order to investigate the efficacy of the triple combination of radiation (SBRT), PD-1 blockade, and OX40 co-stimulation in a syngeneic murine model using ‘immunologically cold’ triple-negative breast cancer cells. SBRT can induce immunogenic tumor cell deaths and act as an in situ vaccine while OX40 signaling has been shown to improve anticancer immunity combined with PD-1 inhibition via multiple preclinical studies. In our study, triple combination therapy significantly improved primary/abscopal tumor control and reduced lung metastases compared to single or dual therapies. This was found to be through an increased ratio of CD8+ T cells to regulatory T cells and a reduced proportion of exhausted T cells in the tumor microenvironment. Abstract Immune checkpoint inhibitors have been successful in a wide range of tumor types but still have limited efficacy in immunologically cold tumors, such as breast cancers. We hypothesized that the combination of agonistic anti-OX40 (α-OX40) co-stimulation, PD-1 blockade, and radiotherapy would improve the therapeutic efficacy of the immune checkpoint blockade in a syngeneic murine triple-negative breast cancer model. Murine triple-negative breast cancer cells (4T1) were grown in immune-competent BALB/c mice, and tumors were irradiated with 24 Gy in three fractions. PD-1 blockade and α-OX40 were administered five times every other day. Flow cytometric analyses and immunohistochemistry were used to monitor subsequent changes in the immune cell repertoire. The combination of α-OX40, radiotherapy, and PD-1 blockade significantly improved primary tumor control, abscopal effects, and long-term survival beyond 2 months (60%). In the tumor microenvironment, the ratio of CD8+ T cells to CD4 + FOXP3+ regulatory T cells was significantly elevated and exhausted CD8+ T cells (PD-1+, CTLA-4+, TIM-3+, or LAG-3+ cells) were significantly reduced in the triple combination group. Systemically, α-OX40 co-stimulation and radiation significantly increased the CD103+ dendritic cell response in the spleen and plasma IFN-γ, respectively. Together, our results suggest that the combination of α-OX40 co-stimulation and radiation is a viable approach to overcome therapeutic resistance to PD-1 blockade in immunologically cold tumors, such as triple-negative breast cancer.
| S-EPMC9179485 | biostudies-literature
Project description:BackgroundImmune-related adverse effects (irAEs) often occur during immune checkpoint inhibitor (ICI) therapy. In the nervous system, the incidence of irAEs ranges from 0.1-12%, with 80% occurring within the first 4 months of ICI application. For complications of the nervous system, adequate diagnosis is made by signs, symptoms, imaging and cerebrospinal fluid. If severe irAEs occur, ICIs should be discontinued and patients should be treated with high-dose glucocorticoids, immunoglobulins, or immunosorbent therapy with systemic support. Patients who develop severe neurologic irAEs have a poorer prognosis.Case descriptionIn this article, we report 2 cases of encephalopathy induced by anti-programmed cell death protein 1 (PD-1) monoclonal antibodies at the initial diagnoses. Our findings may help clinicians to differentiate between encephalopathy caused by immunotherapy and other neurological disorders. Case 1 was a 24-year-old male patient who had undergone PD-1 immunotherapy to treat olfactory neuroblastoma. After the 6th course of therapy, he began to develop persistent epilepsy, which decreased significantly after high doses of glucocorticoid and immunosorbent therapy were administered. Based on his medical history and laboratory examination results, PD-1-induced encephalopathy was the most likely diagnosis. Case 2 was a 67-year-old female patient who had been treated with PD-1/programmed death ligand-1 therapy for lung adenocarcinoma. She began to have headaches after 1 cycle of treatment, and her cognitive function gradually decreased with the continuation of immunotherapy.ConclusionsThese case reports show the difficulty in distinguishing PD-1-induced encephalopathy from other neurological disorders, especially paraneoplastic neurological syndromes. If not treated properly, patients' lives may be endangered. Thus, early identification and early treatment are very important.
| S-EPMC10928638 | biostudies-literature