Identification of mammalian target of rapamycin as a direct target of fenretinide both in vitro and in vivo

Xie, Hua; Zhu, Feng; Huang, Zunnan; Lee, Mee-Hyun; Kim, Dong Joon; Li, Xiang; Lim, Do Young; Jung, Sung Keun; Kang, Soouk; Li, Haitao; Reddy, Kanamata; Wang, Lei; Ma, Weiya; Lubet, Ronald A.; Bode, Ann M.; Dong, Zigang

doi:10.1093/carcin/bgs234

Cited by 17 publications

(13 citation statements)

References 35 publications

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“…5). The chosen dose of HPR (40 mg/kg), shown previously to be effective when used three times per week to slow down growth of A549 xenograft mouse model [21], was found not curative with mouse SCCVII tumors upon use in a single dose. However, this HPR treatment produced a significant improvement in tumor cure rates when combined with a PDT dose that was marginally curative when used alone (Fig.…”

Section: Resultsmentioning

confidence: 99%

Enhanced apoptotic cancer cell killing after Foscan photodynamic therapy combined with fenretinide via de novo sphingolipid biosynthesis pathway

Boppana

DeLor

Buren

et al. 2016

Journal of Photochemistry and Photobiology B: Biology

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We and others have shown that stresses, including photodynamic therapy (PDT)1, can disrupt the de novo sphingolipid biosynthesis pathway, leading to changes in the levels of sphingolipids, and subsequently, modulation of cell death. The de novo sphingolipid biosynthesis pathway includes a ceramide synthase-dependent reaction, giving rise to dihydroceramide, which is then converted in a desaturase-dependent reaction to ceramide. In this study we tested the hypothesis that combining Foscan-mediated PDT with desaturase inhibitor fenretinide (HPR) enhances cancer cell killing. We discovered that by subjecting SCC19 cells, a human head and neck squamous cell carcinoma cell line, to PDT+HPR resulted in enhanced accumulation of C16-dihydroceramide, not ceramide. Concomitantly, mitochondrial depolarization was enhanced by the combined treatment. Enhanced activation of caspase-3 after PDT +HPR was inhibited by FB. Enhanced clonogenic cell death after the combination was sensitive to FB, as well as Bcl2- and caspase inhibitors. Treatment of mouse SCCVII squamous cell carcinoma tumors with PDT+HPR resulted in improved long-term tumor cures. Overall, our data showed that combining PDT with HPR enhanced apoptotic cancer cell killing and antitumor efficacy of PDT. The data suggest the involvement of the de novo sphingolipid biosynthesis pathway in enhanced apoptotic cell killing after PDT+HPR, identify PDT+HPR as a more effective combination than either treatment alone, and that the combination has potential for cancer treatment.

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Section: Resultsmentioning

confidence: 99%

Enhanced apoptotic cancer cell killing after Foscan photodynamic therapy combined with fenretinide via de novo sphingolipid biosynthesis pathway

Boppana

DeLor

Buren

et al. 2016

Journal of Photochemistry and Photobiology B: Biology

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“…4-HPR is known to have multiple targets, some of which overlap with naturally occurring retinoids (39). These include the retinoic acid receptors (RARs) (53,54), retinol-binding proteins (RBPs) (39,55), mammalian target of rapamycin (mTor) (56), and dihydroceramide desaturase (DES) (29,31,57,58), among others. Because we found that all-trans retinoic acid (ATRA) and other analogs of ATRA did not inhibit DENV-2 (see Fig.…”

Section: Resultsmentioning

confidence: 99%

The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication

Carocci

Hinshaw

Rodgers

et al. 2015

Antimicrob Agents Chemother

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Dengue virus (DENV) is a mosquito-borne pathogen that is the causative agent of dengue fever. Severe dengue virus infection is potentially fatal due to hemorrhaging, plasma leakage, and pulmonary shock. The four serotypes of DENV (DENV-1 to DENV-4) are defined by antigenic differences on the viral envelope protein, E, and together, they comprise a species within the Flavivirus genus of the Flaviviridae family. This family of small enveloped viruses with positive-sense RNA genomes encompasses other human pathogens, including West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), and hepatitis C virus (HCV). A recent evidence-based study suggests that approximately 300 million DENV infections occur annually (1), and no vaccine or specific antiviral drug is currently available to treat it. DENV vaccine development is a major challenge due to the antibody-dependent enhancement of infection, a phenomenon in which neutralizing antibodies against one DENV serotype can exacerbate disease upon subsequent infection with another serotype (2, 3). A parallel exploration of antiviral strategies to combat DENV infection is therefore crucial.Resistance to antiviral drugs that act against viral targets occurs rapidly due to the intrinsically high mutation rate of RNA virus polymerases. Host-targeted antivirals that can complement these more traditional antivirals may make the acquisition of resistance to antiviral drugs much less likely and may also offer broad-spectrum activity against phylogenetically related viruses. The interactions between DENV and host lipid biosynthetic, metabolic, trafficking, and signal transducing pathways represent a rich and largely unexplored class of targets for host-targeted antiviral strategies. DENV and other RNA viruses rely entirely on host lipids to supply the membranes essential for the viral replication cycle, and the interaction of viruses with lipid-related processes in the host cell is highlighted by recent studies documenting specific perturbations of these pathways by viruses (4). In addition, so-called bioactive lipids can regulate cellular processes by modulating signal transduction cascades that may impinge on viral infection. Thus, small molecules that act on host-cell lipid signaling and metabolism are attractive as potential anti-DENV compounds.To pursue the strategy of targeting host lipid metabolic and signaling pathways important for DENV infection, we screened a panel of bioactive lipids and small-molecule inhibitors of lipid metabolism for activity against DENV. We chose a library enriched for compounds with known safety and bioavailability profiles to increase our likelihood of identifying clinically useful anti-DENV compounds. We present here the identification of the bioactive lipid 4-hydroxyphenyl retinamide (4-HPR) as an inhib-

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“…Both FEN exposure and dihydroceramides accumulation can initiate cellular survival pathways such as the ER stress response and autophagy induction [39,[44][45][46]. FEN has also been reported to inhibit the kinase activity of mammalian target of rapamycin (mTOR) both in vitro and in vivo [47]. This may possibly occur through the direct binding of FEN to the ATP pocket of mTOR, based on computer modelling of the crystal structure of PI3K-delta [47].…”

Section: Mtor and Autophagy A Cell Survival Mechanismmentioning

confidence: 99%

“…FEN has also been reported to inhibit the kinase activity of mammalian target of rapamycin (mTOR) both in vitro and in vivo [47]. This may possibly occur through the direct binding of FEN to the ATP pocket of mTOR, based on computer modelling of the crystal structure of PI3K-delta [47]. Since mTOR is a key inhibitor of autophagy, inhibition of mTOR by FEN may result in an increase in autophagy induction.…”

Section: Mtor and Autophagy A Cell Survival Mechanismmentioning

confidence: 99%

The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes

Mody

Mcilroy

2014

Biochemical Pharmacology

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Fenretinide remains the most investigated retinoid compound for the prevention of cancer. Its clinical use remains a genuine possibility due to a favourable toxicological profile and accumulation in fatty tissues. Like other well-characterised pharmacological therapies, Fenretinide has been shown to affect multiple signalling pathways. Recent findings have discovered additional beneficial properties the synthetic retinoid was not intentionally designed for, including the prevention of high-fat diet-induced obesity and insulin resistance. These preclinical findings in rodents are timely since obesity has reached pandemic proportions and safe effective therapeutics are severely lacking. Recent investigations have proposed various mechanisms of action for the beneficial effects of Fenretinide. This review covers the current knowledge about Fenretinide's use as a therapy for cancer and potential to treat obesity, insulin resistance and glucose intolerance. An overview of the signalling pathways manipulated by Fenretinide including retinoid homeostasis, reactive oxygen species generation and inhibition of ceramide synthesis will be presented and insights into apoptosis and/or autophagy induction by Fenretinide will also be discussed. The largely unexplored area of Fenretinide metabolites as alternative therapeutic options and how these may be relevant will also be presented. Fenretinide shows great promise, but unfortunately evidence is lacking from clinical trials on Fenretinide's effectiveness in humans. Finally we identify what action can be taken to further progress the investigation of this extremely important retinoid.

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Identification of mammalian target of rapamycin as a direct target of fenretinide both in vitro and in vivo

Cited by 17 publications

References 35 publications

Enhanced apoptotic cancer cell killing after Foscan photodynamic therapy combined with fenretinide via de novo sphingolipid biosynthesis pathway

Enhanced apoptotic cancer cell killing after Foscan photodynamic therapy combined with fenretinide via de novo sphingolipid biosynthesis pathway

The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication

The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes

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