Paclitaxel-induced apoptosis in Jurkat, a leukemic T cell line, is enhanced by ceramide

Myrick, Dorkina; Blackinton, Dilshad; Klostergaard, Jim; Kouttab, Nicola; Maizel, Abby; Wanebo, Harold J.; Mehta, Shashi

doi:10.1016/s0145-2126(99)00048-x

Cited by 45 publications

(21 citation statements)

References 42 publications

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“…The levels of intracellular pro-apoptotic ceramide were shown to be increased by anticancer drugs and stresses in cancer cells (Hannun 1996;Okazaki et al 1998;Sawai et al 1997). It was also shown previously by diVerent groups that increased ceramide levels enhance the eYcacy of vinblastine , Adriamycin, daunorubicin, actinomycin D (Bose et al 1995;Dbaibo et al 1998;Liu et al 1999), and taxol (Myrick et al 1999).…”

Section: Introductionsupporting

confidence: 55%

Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation

Baran

Bielawski

Gündüz

et al. 2011

J Cancer Res Clin Oncol

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Purpose Drug resistance presents a major obstacle for the treatment of some patients with chronic myeloid leukemia (CML). Pro-apoptotic ceramide mediates imatinib-induced apoptosis, and metabolism of ceramide by glucosylceramide synthase (GCS) activity, converting ceramide to glucosyl ceramide, might contribute to imatinib resistance. In this study, we investigated the role of ceramide metabolism by GCS in the regulation of imatinib-induced apoptosis in drug-sensitive and drug-resistant K562 and K562/IMA-0.2 and K562/IMA-1 human CML cells, which exhibit about 2.3-and 19-fold imatinib resistance, respectively. Methods Cytotoxic eVects of PDMP and imatinib were determined by XTT cell proliferation assay. Expression levels of GCS were determined by RT-PCR and western blot. Intracellular ceramide levels were determined by LC-MS. Cell viability analyses was conducted by Trypan blue dye exclusion assay. Cell cycle and apoptosis analyses were examined by Xow cytometry. Results We Wrst showed that mRNA and protein levels of GCS are increased in drug-resistant K562/IMA as compared to sensitive K562 cells. Next, forced expression of GCS in sensitive K562 cells conferred resistance to imatinib-induced apoptosis. In reciprocal experiments, targeting GCS using its known inhibitor, PDMP, enhanced ceramide accumulation and increased cell death in response to imatinib in K562/IMA cells. Conclusion Our data suggest the involvement of GCS in resistance to imatinib-induced apoptosis, and that targeting GCS by PDMP increased imatinib-induced cell death in drug-sensitive and drug-resistant K562 cells via enhancing ceramide accumulation.

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Section: Introductionsupporting

confidence: 55%

Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation

Baran

Bielawski

Gündüz

et al. 2011

J Cancer Res Clin Oncol

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“…23 Nanoliposomes have been tested to deliver short-chain ceramides both in vitro and in vivo, but their use is limited by the relatively high concentration of nanoliposome ceramide (∼1–4 μ g/mL in vitro 22,24 and ∼10–50 mg/kg in vivo 20,25,26 ) required to achieve antitumor effects, leading to possible off-target toxicity. However, as demonstrated by our previous studies, 17,27,28 the levels of ceramide required to kill cancer cells can be substantially reduced by combination therapy with paclitaxel, which interacts with ceramide in a supra-additive manner to promote apoptosis. As carbon nanotubes allow the encapsulation of multiple drugs, they may facilitate the delivery of ceramide at a smaller dosage, resulting in less toxic effects than current delivery methods.…”

mentioning

confidence: 65%

Trojan-Horse Nanotube On-Command Intracellular Drug Delivery

Cao

Kim³

et al. 2012

Nano Lett.

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A major challenge to nanomaterial-based medicine is the ability to release drugs on-command. Here, we describe an innovative drug delivery system based on carbon nanotubes (CNTs), in which compounds can be released inside cells from within the nanotube “on-command” by inductive heating with an external alternating current or pulsed magnetic field. Without inductive heating the drug remains safely inside the CNTs, showing no toxicity in cell viability tests. Similar to the “Trojan-Horse” in function, we demonstrate the delivery of a combination of chemotherapeutic agents with low aqueous solubility, paclitaxel (Taxol), and C6-ceramide, to multidrug resistant pancreatic cancer cells. Nanotube encapsulation permitted the drugs to be used at a 100-fold lower concentration compared to exogenous treatment yet achieve a comparable ∼70% cancer kill rate.

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“…Jurkat cells treated concomitantly with ceramide and paclitaxel displayed a higher level of apoptosis [201]. Nanoparticles containing paclitaxel and C 6 ceramide were more effective at inhibiting the proliferation of aortic smooth muscle cells than with paclitaxel alone [202].…”

Section: Part 3 the Effect Of Sphingolipids On Cancer Treatmentmentioning

confidence: 99%

Evolving concepts in cancer therapy through targeting sphingolipid metabolism

Truman

Garcı́a-Barros

Obeid

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

111

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Traditional methods of cancer treatment are limited in their efficacy due to both inherent and acquired factors. Many different studies have shown that the generation of ceramide in response to cytotoxic therapy is generally an important step leading to cell death. Cancer cells employ different methods to both limit ceramide generation and to remove ceramide in order to become resistant to treatment. Furthermore, sphingosine kinase activity, which phosphorylates sphingosine the product of ceramide hydrolysis, has been linked to multidrug resistance, and can act as a strong survival factor. This review will examine several of the most frequently used cancer therapies and their effect on both ceramide generation and the mechanisms employed to remove it. The development and use of inhibitors of sphingosine kinase will be focused upon as an example of how targeting sphingolipid metabolism may provide an effective means to improve treatment response rates and reduce associated treatment toxicity.

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Paclitaxel-induced apoptosis in Jurkat, a leukemic T cell line, is enhanced by ceramide

Cited by 45 publications

References 42 publications

Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation

Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation

Trojan-Horse Nanotube On-Command Intracellular Drug Delivery

Evolving concepts in cancer therapy through targeting sphingolipid metabolism

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