Cytotoxicity and Apoptosis Enhancement in Brain Tumor Cells Upon Coadministration of Paclitaxel and Ceramide in Nanoemulsion Formulations

Desai, Ankita R.; Vyas, Tushar K.; Amiji, Mansoor M.

doi:10.1002/jps.21182

Cited by 109 publications

(51 citation statements)

References 38 publications

(37 reference statements)

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“…[24][25][26][27] It has been also reported that intranasal administration of micro/nanoemulsions could have a brain-targeting effect. [28][29][30][31][32][33][34][35][36][37] In the present study, we confirmed that a CLA-PTX microemulsion administered intravenously could also produce antitumor activity in brain tissue.…”

Section: Discussionsupporting

confidence: 85%

Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings

Li¹,

Yang²,

Li³

et al. 2012

IJN

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Background: Considering the observations that linoleic acid conjugated with paclitaxel (CLA-PTX) possesses antitumor activity against brain tumors, is able to cross the blood-brain barrier, but has poor water solubility, the purpose of this study was to prepare a novel CLA-PTX microemulsion and evaluate its activity against brain tumors in vitro and in vivo. Methods: The in vitro cytotoxicity of a CLA-PTX microemulsion was investigated in C6 glioma cells. The in vivo antitumor activity of the CLA-PTX microemulsion was evaluated in tumorbearing nude mice and rats. The pharmacokinetics of the CLA-PTX microemulsion were investigated in rats, and its safety was also evaluated in mice. Results: The average droplet size of the CLA-PTX microemulsion was approximately 176.3 ± 0.8 nm and the polydispersity index was 0.294 ± 0.024. In vitro cytotoxicity results showed that the IC 50 of the CLA-PTX microemulsion was 1.61 ± 0.83 µM for a C6 glioma cell line, which was similar to that of free paclitaxel and CLA-PTX solution (P . 0.05). The antitumor activity of the CLA-PTX microemulsion against brain tumors was confirmed in our in vivo C6 glioma tumor-bearing nude mice as well as in a rat model. In contrast, Taxol ® had almost no significant antitumor effect in C6 glioma tumor-bearing rats, but could markedly inhibit growth of C6 tumors in C6 glioma tumor-bearing nude mice. The pharmacokinetic results indicated that CLA-PTX in solution has a much longer circulation time and produces higher drug plasma concentrations compared with the CLA-PTX microemulsion. The results of the acute toxicity study showed that the LD 50 of CLA-PTX solution was 103.9 mg/kg. In contrast, the CLA-PTX microemulsion was well tolerated in mice when administered at doses up to 200 mg/kg. Conclusion: CLA-PTX microemulsion is a novel formulation with significant antitumor efficacy in the treatment of brain tumors, and is safer than CLA-PTX solution.

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Section: Discussionsupporting

confidence: 85%

Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings

Li¹,

Yang²,

Li³

et al. 2012

IJN

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“…Accumulating ceramide levels by molecular and/or biochemical methods has proved to increase apoptotic effects of different chemotherapeutic agents in various types of cancers [17,23]. Combination of short chain ceramide with paclitaxel increased therapeutic efficiency in both sensitive and multidrug resistant ovarian cancer cells [9,23]. Application of cell-permeable exogenous C6-ceramide sensitized different types of cancer cells to doxorubicin [24].…”

Section: Discussionmentioning

confidence: 99%

Bioactive sphingolipids in docetaxel-induced apoptosis in human prostate cancer cells

Bassoy

Baran

2012

Biomedicine & Pharmacotherapy

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In this study, we examined the possible roles of ceramide/sphingosine-1-phosphate and ceramide/glucosyleceramide signaling in docetaxel-induced apoptosis by examining expression levels of the glucosyleceramide synthase and sphingosine kinase-1 and ceramide synthase gene family. As confirmed by isobologram analysis, docetaxel in combination with agents that increase intracellular ceramide levels increased the cytotoxic and apoptotic effects of docetaxel synergistically. More importantly, RT-PCR results revealed that expression levels of glucosyleceramide synthase and sphingosine kinase-1 were downregulated and ceramide synthase genes were upregulated in response to docetaxel. This study identifies mechanisms underlying the involvement of ceramide metabolizing genes in docetaxel-induced apoptosis in prostate cancer cells. © 2012 Elsevier Masson SAS.TUBITAK project number 109S215 and Turkish Academy of Sciences Outstanding Young Investigator Programm

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“…14 In addition, other nanodelivery systems such as polymeric micelles, hydrogels, and liposomes were also reported to effectively deliver PTX for cancer therapy. 15 In colon cancer, several previous studies have shown that PTX could induce remarkable G2/M phase arrest 16 and the activation of caspase 8 apoptosis pathway 17 in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…37 This process facilitates PTX entry to cells and induction of higher cytotoxicity. So far, NE-PTX has been tested only with the drugs ceramide 14 and curcumin 11,38 as a combination treatment for ovarian and brain cancer cells, in which PTX has been shown to have a synergistic effect with these drugs. In our study, we examined the effect of NE-PTX on HCT-116 and HT-29 colon cancer cells in combination with NE-BEZ235, and we found a similar synergistic effect.…”

mentioning

confidence: 99%

Synergistic inhibition of colon cancer cell growth with nanoemulsion-loaded paclitaxel and PI3K/mTOR dual inhibitor BEZ235 through apoptosis

Zou¹,

Li²,

Carcedo³

et al. 2016

IJN

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Colon cancer is the third most common cancer in the world, with drug resistance and metastasis being the major challenges to effective treatments. To overcome this, combination therapy with different chemotherapeutics is a common practice. In this study, we demonstrated that paclitaxel (PTX) together with BEZ235 exhibited a synergetic inhibition effect on colon cancer cell growth. Furthermore, nanoemulsion (NE)-loaded PTX and BEZ235 were more effective than the free drug, and a combination treatment of both NE drugs increased the efficiency of the treatments. BEZ235 pretreatment before adding PTX sensitized the cancer cells further, suggesting a synergistic inhibition effect through the phosphatidylinositol-3-kinases/protein kinase B/mammalian target of rapamycin pathway. The 50% inhibitory concentrations for BEZ235 were 127.1 nM and 145.0 nM and for PTX 9.7 nM and 9.5 nM for HCT-116 and HT-29 cells, respectively. When loaded with NE the 50% inhibitory concentrations for BEZ235 decreased to 52.6 nM and 55.6 nM and for PTX to 1.9 nM and 2.3 nM for HCT-116 and HT-29 cells, respectively. Combination treatment with 10 nM NE-BEZ235 and 0.6 nM and 1.78 nM NE-PTX could kill 50% of HCT-116 and HT-29, respectively. The cell death caused by the treatment was through apoptotic cell death, which coincided with decreased expression of anti-apoptotic protein B-cell lymphoma 2. Our data indicate that the combination therapy of PTX with the phosphatidylinositol-3-kinases/protein kinase B/mammalian target of rapamycin dual inhibitor BEZ235 using NE delivery may hold promise for a more effective approach for colon cancer treatment.

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Cytotoxicity and Apoptosis Enhancement in Brain Tumor Cells Upon Coadministration of Paclitaxel and Ceramide in Nanoemulsion Formulations

Cited by 109 publications

References 38 publications

Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings

Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings

Bioactive sphingolipids in docetaxel-induced apoptosis in human prostate cancer cells

Synergistic inhibition of colon cancer cell growth with nanoemulsion-loaded paclitaxel and PI3K/mTOR dual inhibitor BEZ235 through apoptosis

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