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

نویسندگان

  • Daniel Dindo
  • Felix Dahm
  • Zdzislaw Szulc
  • Alicja Bielawska
  • Lina M Obeid
  • Yusuf A Hannun
  • Rolf Graf
  • Pierre-Alain Clavien
چکیده

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 [omega-pyridinium bromide D-erythro-C16-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 C16-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.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy

Mechanisms by which autophagy promotes cell survival or death are unclear. We provide evidence that C(18)-pyridinium ceramide treatment or endogenous C(18)-ceramide generation by ceramide synthase 1 (CerS1) expression mediates autophagic cell death, independent of apoptosis in human cancer cells. C(18)-ceramide-induced lethal autophagy was regulated via microtubule-associated protein 1 light ch...

متن کامل

LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria.

Treatment of pancreatic cancer that cannot be surgically resected currently relies on minimally beneficial cytotoxic chemotherapy with gemcitabine. As the fourth leading cause of cancer-related death in the United States with dismal survival statistics, pancreatic cancer demands new and more effective treatment approaches. Resistance to gemcitabine is nearly universal and appears to involve def...

متن کامل

Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells.

The sphingolipid ceramide has been recognized as an important second messenger implicated in regulating diverse signaling pathways especially for apoptosis. Very little is known, however, about the molecular mechanisms underlying nonapoptotic cell death induced by ceramide. In the present study, we first demonstrate that ceramide induces nonapoptotic cell death in malignant glioma cells. The ce...

متن کامل

A study on the targeting of ceramide metabolism by (-)-epicatechin gallate, catechin and quercetin in A-549 lung cancer cell line

Catechin, epicatechin gallate (ECG) and quercetin, as bioactive flavonoids, have been shown to possess anticarcinogenic effects. Ceramide plays an important role in killing tumor cells. Accordingly, the aim of this study was to clarify the involvement of these compounds in ceramide metabolism in A549 cancerous cell line. Spectrophotometer, cell culture and HPLC methods were used. Cell viability...

متن کامل

Induction of Apoptosis by extract of Persian Gulf Marine Mollusk, Turbo coronatus through the ROS-Mediated Mitochondrial Targeting on Human Epithelial Ovarian Cancer Cells

Despite recent improvements in treatment, ovarian cancer is still the leading cause of death from gynaecological malignancies. Today, marine mollusks are considered as natural source of new biologically and pharmacologically active compounds by scientists and the pharmaceutical industries. The aim of this study is to investigate the selective apoptotic effects of Turbo coronatus crude extract f...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Molecular cancer therapeutics

دوره 5 6  شماره 

صفحات  -

تاریخ انتشار 2006