Inhibition of growth and telomerase activity by novel cationic ceramide analogs with high solubility in human head and neck squamous cell carcinoma cells

Rossi, Michael J.; Sundararaj, Kamala; Koybasi, Serap; Phillips, Monique; Szulc, Zdzislaw M.; Bielawska, Alicja; Day, Terry A.; Obeid, Lina M.; Hannun, Yusuf A.; Öğretmen, Besim

doi:10.1016/j.otohns.2004.08.015

Cited by 47 publications

(44 citation statements)

References 16 publications

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“…This synergistic action was also evident in an overadditive increase of caspase-3 and caspase-9 activity and the number of cells with dissipated Dc m , suggesting mitochondria to be a target of doxorubicin in SW403 cells. This phenomenon has also been recently described using short-chain pyridinium ceramides and doxorubicin in HepG2 cells (53). However, in our hands, doxorubicin did not induce any alteration in endogenous ceramide levels in the cellular fractions analyzed (mitochondrial, cytosolic, and extramitochondrial).…”

Section: Discussionsupporting

confidence: 89%

Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells

Dindo

Dahm

Szulc

et al. 2006

Molecular Cancer Therapeutics

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Ceramides are sphingolipid second messengers that are involved in the mediation of cell death. There is accumulating evidence that mitochondria play a central role in ceramide-derived toxicity. We designed a novel cationic long-chain ceramide [W-pyridinium bromide D-erythro -C 16 -ceramide (LCL-30)] targeting negatively charged mitochondria. Our results show that LCL-30 is highly cytotoxic to SW403 cells (and other cancer cell lines) and preferentially accumulates in mitochondria, resulting in a decrease of the mitochondrial membrane potential, release of mitochondrial cytochrome c, and activation of caspase-3 and caspase-9. Ultrastructural analyses support the concept of mitochondrial selectivity. Interestingly, levels of endogenous mitochondrial C 16 -ceramide decreased by more than half, whereas levels of sphingosine-1-phosphate increased dramatically and selectively in mitochondria after administration of LCL-30, suggesting the presence of a mitochondrial sphingosine kinase. Of note, intracellular long-chain ceramide levels and sphingosine-1-phosphate remained unaffected in the cytosolic and extramitochondrial (nuclei/cellular membranes) cellular fractions. Furthermore, a synergistic effect of cotreatment of LCL-30 and doxorubicin was observed, which was not related to alterations in endogenous ceramide levels.Cationic long-chain pyridinium ceramides might be promising new drugs for cancer therapy through their mitochondrial preference. [Mol Cancer Ther 2006;5(6):1520 -9]

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Section: Discussionsupporting

confidence: 89%

Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells

Dindo

Dahm

Szulc

et al. 2006

Molecular Cancer Therapeutics

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“…The accumulation of D-erythro-C 6 -Pyr-Cer specifically in mitochondria has been confirmed recently, and the data showed that mitochondrial localization of Pyr-Cer caused a decrease in its membrane potential, leading to cytochrome C release and apoptosis (Novgorodov et al, 2005). In another independent study, antiproliferative responses of L-t-C 6 -Pyr-Cer, such as inhibition of cell cycle and telomerase activity, in HNSCC cell lines, but not in noncancerous human adult keratinocytes and Wi-38 lung fibroblasts, were demonstrated (Rossi et al, 2005). The improved effects of L-t-C 6 -Pyr-Cer in combination with gemcitabine (GMZ) in the inhibition of cell growth were also shown in HNSCC cells in vitro (Rossi et al, 2005).…”

mentioning

confidence: 76%

“…To overcome these problems, many biophysical and chemical approaches have been developed with improved delivery and bioavailability (Shabbits and Mayer, 2003;Stover and Kester, 2003). Another alternative approach has been the development of novel pyridinium ceramide analogs with increased water solubility, cell membrane permeability, and cellular uptake compared with their uncharged conventional ceramides (Novgorodov et al, 2005;Rossi et al, 2005). Pyridinium ceramides are designed to preferentially localize into negatively charged intracellular compartments, specifically mitochondria and nucleus, due to the presence of a positive charge delocalized over the -electron system.…”

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confidence: 99%

Potent Antitumor Activity of a Novel Cationic Pyridinium-Ceramide Alone or in Combination with Gemcitabine against Human Head and Neck Squamous Cell Carcinomas in Vitro and in Vivo

Senkal¹,

Ponnusamy²,

Rossi³

et al. 2006

J Pharmacol Exp Ther

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In this study, a cationic water-soluble ceramide analog L-threo-C 6 -pyridinium-ceramide-bromide (L-t-C 6 -Pyr-Cer), which exhibits high solubility and bioavailability, inhibited the growth of various human head and neck squamous cell carcinoma (HNSCC) cell lines at low IC 50 concentrations, independent of their p53 status. Consistent with its design to target negatively charged intracellular compartments, L-t-C 6 -Pyr-Cer accumulated mainly in mitochondria-, and nuclei-enriched fractions upon treatment of human UM-SCC-22A cells [human squamous cell carcinoma (SCC) of the hypopharynx] at 1 to 6 h. In addition to its growth-inhibitory function as a single agent, the supra-additive interaction of L-t-C 6 -Pyr-Cer with gemcitabine (GMZ), a chemotherapeutic agent used in HNSCC, was determined using isobologram studies. Then, the effects of this ceramide, alone or in combination with GMZ, on the growth of UM-SCC-22A xenografts in SCID mice was assessed following the determination of preclinical parameters, such as maximum tolerated dose, clearance from the blood, and bioaccumulation. Results demonstrated that treatment with L-t-C 6 -PyrCer in combination with GMZ significantly prevented the growth of HNSCC tumors in vivo. The therapeutic efficacy of L-t-C 6 -Pyr-Cer/ GMZ combination against HNSCC tumors was approximately 2.5-fold better than that of the combination of 5-fluorouracil/cisplatin. In addition, liquid chromatography/mass spectroscopy analysis showed that the levels of L-t-C 6 -Pyr-Cer in HNSCC tumors weresignificantly higher than its levels in the liver and intestines; interestingly, the combination with GMZ increased the sustained accumulation of this ceramide by approximately 40%. Moreover, treatment with L-t-C 6 -Pyr-Cer/GMZ combination resulted in a significant inhibition of telomerase activity and decrease in telomere length in vivo, which are among downstream targets of ceramide.Human head and neck squamous cell carcinomas (HNSCCs) are among the five most common cancers in the world. Global occurrence of HNSCC is high, and it is estimated that approximately 780,000 new patients are diagnosed with HNSCC each year in the adult population. There are approximately 41,000 new HNSCC cases diagnosed annually in the United States in 2004, and the overall 5-year survival of patients with stage III and IV disease remains less than 50% (Her, 2001;Jemal et al., 2004).Historically, chemotherapy did not play a curative role in the treatment of HNSCC but was reserved for palliative therapy. Surgery and radiation therapy remained the primary curative options; however, complications of these ther-

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“…After 24 h, cells were incubated with different concentrations of C 6 -pyridinium ceramide or C 6 -ceramide for specifi ed times. The IC 50 of each compound was determined from cell growth plots ( 26 ). For Trypan blue exclusion assay, MCF7 cells were plated onto 6-well plates (1 × 10 5 cells/plate) and then treated with 10 M C 6 -pyridinium ceramide or C 6 -ceramide for specifi ed times.…”

Section: Mtt and Trypan Blue Exclusion Assaysmentioning

confidence: 99%

Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis

Hou

Jin

Zhou

et al. 2011

Journal of Lipid Research

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Inhibition of growth and telomerase activity by novel cationic ceramide analogs with high solubility in human head and neck squamous cell carcinoma cells

Abstract: These data suggest that the novel C6-Pyr-Cer with high solubility and bioavailability may lead to the development of new therapeutic strategies that target telomerase for the treatment of HNSCC.

Cited by 47 publications

References 16 publications

Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells

Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells

Potent Antitumor Activity of a Novel Cationic Pyridinium-Ceramide Alone or in Combination with Gemcitabine against Human Head and Neck Squamous Cell Carcinomas in Vitro and in Vivo

Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis

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