The antineoplastic properties of <scp>FTY</scp>720: evidence for the repurposing of fingolimod

Patmanathan, Sathya Narayanan; Yap, Lee Fah; Murray, Paul G.; Paterson, Ian C.

doi:10.1111/jcmm.12635

Cited by 46 publications

(71 citation statements)

References 108 publications

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“…and Sphingomab 65 may be useful adjunctive antitumor therapies. Several mechanisms are implicated in the observed effects on tumor cells and cancer outcome, including regulation of new blood vessel formation, direct cellular toxicity, and regulation of cellular survival and metabolism 64,65 . Understanding the role of S1P signaling in TDLNs could lead to better-targeted antitumor therapies that promote lymphocyte egress to allow an antitumor immune response.…”

Section: Discussionmentioning

confidence: 99%

Distinct mechanisms of B and T lymphocyte accumulation generate tumor-draining lymph node hypertrophy

et al. 2016

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Tumor-draining lymph nodes (TDLNs) often enlarge in human cancer patients and in murine tumor models, due to lymphocyte accumulation and lymphatic sinus growth. B lymphocytes within TDLNs can drive lymph node hypertrophy in response to tumor growth, however little is known about the mechanisms directing the preferential accumulation of B lymphocytes relative to T cells in enlarging TDLNs. To define why B and T lymphocytes accumulate in TDLNs, we quantified lymphocyte proliferation, apoptosis, entry, and exit in TDLNs versus contralateral non-TDLNs (NTDLNs) in a footpad B16-F10 melanoma mouse model. B and T lymphocyte proliferation and apoptosis were increased as the TDLNs enlarged, although relative rates were similar to those of NTDLNs. TDLN entry of B and T lymphocytes via high endothelial venules was also modestly increased in enlarged TDLNs. Strikingly, the egress of B cells was strongly reduced in TDLNs versus NTDLNs, while T cell egress was modestly decreased, indicating that regulation of lymphocyte exit from TDLNs is a major mechanism of preferential B lymphocyte accumulation. Surface sphingosine-1-phosphate receptor 1 (S1PR1) which binds S1P and signals lymphocyte egress, exhibited greater downregulation in B relative to T lymphocytes, consistent with preferential retention of B lymphocytes in TDLNs. TDLN lymphocytes did not activate surface CD69 expression, indicating a CD69-independent mechanism of downregulation of S1PR1. B and T cell trafficking via afferent lymphatics to enter TDLNs also increased, suggesting a pathway for accumulation of tumor-educated lymphocytes in TDLNs. These mechanisms regulating TDLN hypertrophy could provide new targets to manipulate lymphocyte responses to cancer.

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Section: Discussionmentioning

confidence: 99%

Distinct mechanisms of B and T lymphocyte accumulation generate tumor-draining lymph node hypertrophy

et al. 2016

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“…Fingolimod was shown to inhibit cancer-relevant signal transduction pathways independent of S1PR binding, in part due to its structural similarity to sphingosine. The heterogeneity of responses to fingolimod includes increased cell death, decreased cell proliferation, angiogenesis, migration, invasion, metastasis and inflammation (Patmanathan et al, 2015;White et al, 2016). Thus, by targeting multiple oncogenic signaling pathways and compensatory pathways implicated in drug resistance, fingolimod in principle holds promise for drug repurposing as an anticancer agent for various oncology indications characterized by different molecular abnormalities.…”

Section: S1pr-independent Effects (Off-target)mentioning

confidence: 99%

The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives

Huwiler

Zangemeister‐Wittke

2018

Pharmacology & Therapeutics

175

134

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The immunomodulatory drug fingolimod (FTY720, Gilenya) was approved for oral treatment of relapsing-remitting multiple sclerosis, due to its impressive efficacy and good tolerability. Pharmacologically, it acts as an unselective agonist of sphingosine 1-phosphate receptors (S1PR) and as a selective functional antagonist of the S1P subtype by induction of receptor downregulation. Since S1P is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation and hence immunosuppression. Numerous preclinical studies have since been performed with the aim to increase the spectrum of potential indications for fingolimod with emphasis on other autoimmune disorders and diseases associated with inflammation and uncontrolled cell proliferation, including cancer. As an alternative to fingolimod, novel S1PR modulators with a more selective receptor activation profile and improved pharmacokinetic performance and tolerability have also been developed. Preclinical and clinical studies are ongoing to investigate their therapeutic potential. This review discusses the most relevant preclinical and clinical findings from S1PR-targeting and from less-well defined off-target effects reported in the literature, and reveals perspectives for using fingolimod and functionally-related derivatives and new formulations in the management of an increasing number of diseases.

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“…15,16 Furthermore, some studies have confirmed that blocking autophagy through Beclin 1 siRNA (siBeclin 1) or ATG 5 siRNA (siATG 5) increases cancer cell sensitivity to FTY720. 10,[17][18][19] Gene silencing strategies, particularly RNA interference, have been widely applied to inhibit the expression of cancerrelated proteins. 20,21 Combining drug and siRNA therapy to downregulate cancer-related gene expression, promoting the anticancer drug effects at the tumor site can effectively suppress tumor progression, and an increasing number of studies have focused on using nonviral vectors to co-deliver drugs and siRNA.…”

Section: Introductionmentioning

confidence: 99%

Targeted co-delivery of Beclin 1 siRNA and FTY720 to hepatocellular carcinoma by calcium phosphate nanoparticles for enhanced anticancer efficacy

Wu¹,

Wang²,

Zhang³

et al. 2018

IJN

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PurposeFTY720, known as fingolimod, is a new immunosuppressive agent with effective anticancer properties. Although it was recently confirmed that FTY720 inhibits cancer cell proliferation, FTY720 can also induce protective autophagy and reduce cytotoxicity. Blocking autophagy with Beclin 1 siRNA after treatment with FTY720 promotes apoptosis. The objective of this study was to enhance the anticancer effect of FTY720 in hepatocellular carcinoma (HCC) by targeted co-delivery of FTY720 and Beclin 1 siRNA using calcium phosphate (CaP) nanoparticles (NPs).Materials and methodsFirst, the siRNA was encapsulated within the CaP core. To form an asymmetric lipid bilayer structure, we then used an anionic lipid for the inner leaflet and a cationic lipid for the outer leaflet; after removing chloroform by rotary evaporation, these lipids were dispersed in a saline solution with FTY720. The NPs were analyzed by transmission electron microscopy, dynamic light scattering and ultraviolet–visible spectrophotometry. Cancer cell viability and cell death were analyzed by MTT assays, fluorescence-activated cell sorting analysis and Western blotting. In addition, the in vivo effects of the NPs were investigated using an athymic nude mouse subcutaneous transplantation tumor model.ResultsWhen the CaP NPs, called LCP-II NPs, were loaded with FTY720 and siRNA, they exhibited the expected size and were internalized by cells. These NPs were stable in systemic circulation. Furthermore, co-delivery of FTY720 and Beclin 1 siRNA significantly increased cytotoxicity in vitro and in vivo compared with that caused by treatment with the free drug alone.ConclusionThe CaP NP system can be further developed for co-delivery of FTY720 and Beclin 1 siRNA to treat HCC, enhancing the anticancer efficacy of FTY720. Our findings provide a new insight into HCC treatment with co-delivered small molecules and siRNA, and these results can be readily translated into cancer clinical trials.

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The antineoplastic properties of FTY720: evidence for the repurposing of fingolimod

Cited by 46 publications

References 108 publications

Distinct mechanisms of B and T lymphocyte accumulation generate tumor-draining lymph node hypertrophy

Distinct mechanisms of B and T lymphocyte accumulation generate tumor-draining lymph node hypertrophy

The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives

Targeted co-delivery of Beclin 1 siRNA and FTY720 to hepatocellular carcinoma by calcium phosphate nanoparticles for enhanced anticancer efficacy

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