Effect of rosiglitazone, an insulin sensitizer, on myelotoxicity caused by repeated doses of 5-fluorouracil

Djazayeri, Katayoun; Szilvássy, Zoltán; Benkö, K.; Rozsa, Bernadett; Szabo, Barbara; Aj, Szentmiklósi; Benkö, Ilona

doi:10.1016/j.phrs.2005.10.004

Cited by 4 publications

(2 citation statements)

References 22 publications

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“…It is also consistent with pre-clinical studies in which a PPARÁ agonist, RS5444, enhanced the activity of the cytotoxic drug paclitaxel against anaplastic thyroid carcinoma (37). Interestingly, in other pre-clinical studies, rosiglitazone was found to have myeloprotective effects when given in combination with or following 5-fluorouracil treatment (38,39), while pioglitazone and netoglitazone have been shown to be protective of normal colonic mucosa in a model of colonic injury (40). Thiazolidinediones may therefore have potential benefit in the context of chemotherapeutic combinations both in enhancing the activity of cytotoxic therapeutics and in protecting sensitive normal tissues.…”

Section: Discussionsupporting

confidence: 83%

Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor γ-dependent manner

Richard

Blay²

2007

Int J Oncol

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Peroxisome proliferator activated receptor (PPAR) Á is a nuclear receptor involved primarily in lipid and glucose metabolism. PPARÁ is also expressed in several cancer types, and has been suggested to play a role in tumor progression. PPARÁ agonists have been shown to reduce the growth of colorectal carcinoma cells in culture and in xenograft models. Furthermore, the PPARÁ agonist thiazolidinedione has been shown to reduce metastasis in a murine model of rectal cancer. Since the chemokine receptor CXCR4 has emerged as an important player in tumorigenesis, particularly in the process of metastasis, we sought to determine if PPARÁ agonists might act in part by reducing CXCR4 expression. We found that rosiglitazone, a thiazolidinedione PPARÁ agonist used primarily in the treatment of type 2 diabetes, significantly reduced cell-surface expression of CXCR4 protein on HT-29 human colorectal carcinoma cells. This effect occurred at concentrations as low as 1 nM, and was first evident after 8 h of drug exposure. CXCR4 mRNA was also down-regulated after treatment with rosiglitazone, indicating that the effect occurs at the level of transcription. Four other thiazolidinedione compounds (ciglitazone, pioglitazone, troglitazone, and MCC555) also significantly reduced CXCR4 expression. To confirm the involvement of PPARÁ in thiazolidinedioneinduced CXCR4 down-regulation, we used PPARÁ antagonists GW9662 and T0070907, both of which completely blocked the effect of rosiglitazone on CXCR4 expression. Furthermore, HT-29 cells in which PPARÁ expression was reduced using shRNA were less responsive to rosiglitazone. In conclusion, we have shown that thiazolidinedione compounds reduce CXCR4 mRNA and cell-surface protein expression in a PPARÁ-dependent manner.

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Section: Discussionsupporting

confidence: 83%

Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor γ-dependent manner

Richard

Blay²

2007

Int J Oncol

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“…Therefore, there remains a serious concern that PPARγ agonist ligands might increase the overall toxicities of carboplatin chemotherapy, or that combination dosing in humans might be associated with novel toxicities not seen with either drug individually. Myelosuppression, especially in the form of thrombocytopenia, is the most common side of effect of carboplatin (50, 51). Our data indicate that combination dosing of the PPARγ agonist ligand, rosiglitazone, and carboplatin does not increase the myelosuppression or other toxic effects of carboplatin.…”

Section: Discussionmentioning

confidence: 99%

Regression of Drug-Resistant Lung Cancer by the Combination of Rosiglitazone and Carboplatin

Girnun

Chen

Silvaggi

et al. 2008

Clinical Cancer Research

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Purpose: Current therapy for lung cancer involves multimodality therapies. However, many patients are either refractory to therapy or develop drug resistance. KRAS and epidermal growth factor receptor (EGFR) mutations represent some of the most common mutations in lung cancer, and many studies have shown the importance of these mutations in both carcinogenesis and chemoresistance. Genetically engineered murine models of mutant EGFR and KRAS have been developed that more accurately recapitulate human lung cancer. Recently, using cell-based experiments, we showed that platinum-based drugs and the antidiabetic drug rosiglitazone (PPARg ligand) interact synergistically to reduce cancer cell and tumor growth. Here, we directly determined the efficacy of the PPARg/carboplatin combination in these more relevant models of drug resistant non^small cell lung cancer. Experimental Design: Tumorigenesis was induced by activation of either mutant KRAS or EGFR. Mice then received either rosiglitazone or carboplatin monotherapy, or a combination of both drugs. Change in tumor burden, pathology, and evidence of apoptosis and cell growth were assessed. Results: Tumor burden remained unchanged or increased in the mice after monotherapy with either rosiglitazone or carboplatin. In striking contrast, we observed significant tumor shrinkage in mice treated with these drugs in combination. Immunohistochemical analyses showed that this synergy was mediated via both increased apoptosis and decreased proliferation. Importantly, this synergy between carboplatin and rosiglitazone did not increase systemic toxicity. Conclusions: These data show that the PPARg ligand/carboplatin combination is a new therapy worthy of clinical investigation in lung cancers, including those cancers that show primary resistance to platinum therapy or acquired resistance to targeted therapy.Lung cancer is the leading cause of cancer-related deaths. There are over 210,000 cases of lung cancer diagnosed and over 160,000 deaths in the United States alone (1, 2). The most common type of lung cancer is non -small cell lung cancer (NSCLC), which comprises over 75% of the cases (3). Despite advances in multimodality therapies, <15% of patients with NSCLC survive beyond 5 years of initial diagnosis. Activating mutations of the KRAS proto-oncogene are among the most common genetic alterations in NSCLC (4 -8). These mutations lead to the constitutive activation of downstream signaling transduction pathways including RAF and phosphatidylinositol-3-OH kinase. These pathways, in turn, regulate proliferation and survival. In addition to playing a role in the development of lung cancer, mutations in KRAS predict a poor outcome and a poor response to conventional therapy such as platinumbased drugs, as well as targeted therapy (4, 9 -12). The

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Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus

Géresi

Megyeri

Szabo

et al. 2015

Cancer Chemother Pharmacol

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PurposeSome authors observed increased carboplatin-associated myelotoxicity in obese patients which was exclusively attributed to elevated AUC. To investigate the potential contribution of functional changes of cells primarily responsible for myelopoiesis, granulocyte-macrophage progenitors (CFU-GM) were studied in obesity-associated diabetes mellitus (DMT2). MethodsThe most frequently used animal model of human obesity with DMT2 is db/db mouse. Cellularity, frequency of CFU-GM and total CFU-GM content of femoral bone marrow was measured after 100 mg/kg dose of carboplatin in vivo. To exclude influence of pharmacokinetic changes direct toxicity of carboplatin on CFU-GM was also determined in vitro and was compared with other anticancer agents, namely doxorubicin, 5-fluorouracil and 4-thiouridylate. ResultsAfter intraperitoneal administration of carboplatin, each measured characteristics of bone marrow function were more significantly suppressed and the induced neutropenia were more serious in db/db mice than in the controls. The increased myelotoxicity seemed to be a direct effect on myeloid progenitor cells since their increased in vitro sensitivity was found in db/db mice. This was not specific for carboplatin, a similar double to 5-fold increase in myelotoxicity of each cytotoxic drug with different mechanism of action was observed. Four-thiouridylate, a promising antileukemic molecule with good therapeutic index, was by far the least toxic for CFU-GM of db/db mice.Conclusions A serious disorder of CFU-GM progenitors was suggested in obese mice with DMT2, which eventually might lead to more severe myelotoxicity and neutropenia. Weight loss and normalization of glucose homeostasis may be important before chemotherapy of malignant diseases in obesity with DMT2.

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Effect of rosiglitazone, an insulin sensitizer, on myelotoxicity caused by repeated doses of 5-fluorouracil

Cited by 4 publications

References 22 publications

Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor γ-dependent manner

Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor γ-dependent manner

Regression of Drug-Resistant Lung Cancer by the Combination of Rosiglitazone and Carboplatin

Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus

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