3-Ketone-4,6-diene ceramide analogs exclusively induce apoptosis in chemo-resistant cancer cells

Ponnapakam, Adharsh P.; Liu, Jiawang; Bhinge, Kaustubh N.; Drew, Barbara A.; Wang, Tony L.; Antoon, James W.; Nguyen, Thong Tien; Dupart, Patrick S.; Wang, Yuji; Zhao, Ming; Foroozesh, Maryam; Beckman, Barbara S.

doi:10.1016/j.bmc.2013.12.065

Cited by 17 publications

(15 citation statements)

References 31 publications

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“…Several studies have reported that ceramide is intimately involved in cancer pathogenesis. Alterations in its metabolism are involved in regulation of cancer initiation, progression, and/or response to chemotherapeutic agents and radiation [ 16 , 32 , 33 ]. However, the clinical relevance of ceramide levels in patients with breast cancer remains unclear, due to lack of accurate measurement of ceramides in human patients.…”

Section: Discussionmentioning

confidence: 99%

Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

et al. 2018

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Sphingolipids have emerged as key regulatory molecules in cancer cell survival and death. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients are yet to be revealed. The aim of this study was to investigate the ceramide levels and its biosynthesis pathways in human breast cancer patients. Breast cancer, peri-tumor and normal breast tissue samples were collected from surgical specimens from a series of 44 patients with breast cancer. The amount of sphingolipid metabolites in the tissue were determined by mass spectrometry. The Cancer Genome Atlas was used to analyze gene expression related to the sphingolipid metabolism. Ceramide levels were higher in breast cancer tissue compared to both normal and peri-tumor breast tissue. Substrates and enzymes that generate ceramide were significantly increased in all three ceramide biosynthesis pathways in cancer. Further, higher levels of ceramide in breast cancer were associated with less aggressive cancer biology presented by Ki-67 index and nuclear grade of the cancer. Interestingly, patients with higher gene expressions of enzymes in the three major ceramide synthesis pathways showed significantly worse prognosis. This is the first study to reveal the clinical relevance of ceramide metabolism in breast cancer patients. We demonstrated that ceramide levels in breast cancer tissue were significantly higher than those in normal tissue, with activation of the three ceramide biosynthesis pathways. We also identified that ceramide levels have a significant association with aggressive phenotype and its enzymes have prognostic impact on breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

et al. 2018

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“…Ceramide analog 315 has been previously shown to be anti-proliferative and cytotoxic to human breast cancer cells in vitro [12]. This compound has an imine functional group in the ceramide side-chain, and an amide functional group replacing the allyl alcohol group in the ceramide backbone [9].…”

Section: Discussionmentioning

confidence: 99%

“…1) Extension of the conjugated system in the ceramide backbone and/or side-chain increases the potency; 2) Phenyl imine group modification on the side-chain (especially ortho-substituted phenyl) enhances the anti-cancer potency; 3) 1-Position modification results in GCS (Glucosylceramide Synthase) inhibition; and 4) Ceramides can induce apoptosis and inhibit cell growth and proliferation in in vitro studies [9–12]. Despite recent advances in the treatment of cancer, triple negative breast cancer is very aggressive and difficult to treat [4], posing an important clinical challenge due to unresponsiveness to endocrine- and chemo-therapies.…”

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confidence: 99%

Inhibition of breast tumor growth in mice after treatment with ceramide analog 315

et al. 2018

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The aim of this study was to evaluate the anticancer and antitumor activities of ceramide analog 315 in nude mice. Nude mice (n=10) were injected bilaterally with 5×10 MDA-MB-231 cells on each side. Tumors were allowed to form for 2 weeks. The mice were then divided into two groups (n=5 in each group). The control group mice were injected with 25 μl of dimethyl sulfoxide and the treatment group mice were injected with 10 mg/kg of analog 315 (in dimethyl sulfoxide, 25 μl volume) every day for a period of 3 weeks. Animal weights and tumors were measured every week for 3 weeks. At the end of the experimental period, control animals had retained excess fluid, and showed larger tumor sizes compared with the treated group (2.95 vs. 1.67 g). A 45% reduction in tumor size and 80% decrease in tumor volume were observed in the treatment group. There was a significant increase in the weights of liver (10%) and spleen (19%) between the control and treated animals. Hematoxylin and Eosin staining of MDA-MB-231 tumor sections revealed more acellular necrotic regions in tumors from the treatment groups compared with the ones from the control group. Ki67, a proliferation marker was higher in number in control tumor section (71.8±12.8) compared to the treatment tumor section (37.4±10.4) (P<0.001). Photomicrographs showed metastatic tumor burden in kidney, lungs, and spleen collected from the control group mice bearing MDA-MB-231 tumors. Treatment group mice showed normal microscopic tissue architecture. Overall, our study showed tumor growth inhibition and antimetastatic effects for the novel ceramide analog 315.

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“…21,22 For the synthesis of analog 403, D-sphingosine was reacted with phenylacetyl chloride in the presence of sodium bicarbonate as a base and dichloromethane as solvent to get analog 403. 23…”

Section: New Ceramide Analogs 315 and 403 Synthesismentioning

confidence: 99%

Developing new ceramide analogs and identifying novel sphingolipid-controlled genes against a virus-associated lymphoma

Chen

Goyal

Dai

et al. 2020

Blood

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Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy, usually infected by Kaposi's sarcoma-associated herpesvirus (KSHV), one of human oncogenic viruses. Currently, there is no specific treatment for PEL, therefore developing new therapies is of high importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cells survival. To further develop sphingolipid metabolism targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes, and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death, and identified a subset of novel cellular genes including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.

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3-Ketone-4,6-diene ceramide analogs exclusively induce apoptosis in chemo-resistant cancer cells

Cited by 17 publications

References 31 publications

Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

Inhibition of breast tumor growth in mice after treatment with ceramide analog 315

Developing new ceramide analogs and identifying novel sphingolipid-controlled genes against a virus-associated lymphoma

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