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Switching the sphingolipid rheostat in the treatment of diabetes and cancer comorbidity from a problem to an advantage.

Haass NK, Nassif N, McGowan EM - Biomed Res Int (2015)

Bottom Line: Cancer and diabetes are among the most common diseases in western societies.Epidemiological studies have shown that diabetic patients have a significantly higher risk of developing a number of different types of cancers and that individuals with comorbidity (cancer and diabetes/prediabetes) have a poorer prognosis relative to nondiabetic cancer patients.This paper will highlight some of the complexities inherent in the use of the emerging sphingosine kinase/S1P modulators in the treatment of comorbidity of diabetes and cancer.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia ; The Centenary Institute, Newtown, NSW, Australia ; Discipline of Dermatology, University of Sydney, Camperdown, NSW, Australia.

ABSTRACT
Cancer and diabetes are among the most common diseases in western societies. Epidemiological studies have shown that diabetic patients have a significantly higher risk of developing a number of different types of cancers and that individuals with comorbidity (cancer and diabetes/prediabetes) have a poorer prognosis relative to nondiabetic cancer patients. The increasing frequency of comorbidity of cancer and diabetes mellitus, mainly type 2 diabetes, has driven the development of therapeutic interventions that target both disease states. There is strong evidence to suggest that balancing the sphingolipid rheostat, ceramide--sphingosine--sphingosine-1-phosphate (S1P) is crucial in the prevention of diabetes and cancer and sphingosine kinase/S1P modulators are currently under development for the treatment of cancer and diabetes. This paper will highlight some of the complexities inherent in the use of the emerging sphingosine kinase/S1P modulators in the treatment of comorbidity of diabetes and cancer.

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Balancing the SphK1/S1P rheostat for diabetes and cancer comorbidity treatments. Second generation S1P receptor modulators are currently being developed to target individual and multiple S1P receptors. Each of the receptor modulators binds to individual or multiple receptors to block or activate the S1P receptor. Siponimod is a S1P1,4,5 modulator; ponesimod is an agonist for S1P1,3,4; KRP-203 is an agonist for S1P1,4; ONO-4641 is an agonist for S1P1,4,5; RPC1063 is an agonist for S1P1,4,5; Cs-0777 is an agonist for S1P1,3,5; GSK2018682 is an agonist for S1P1,5. FTY720 and JTE-013 are described in Figure 2. These novel S1P receptors and downstream signalling pathways and functions are reviewed in [88, 93]. Sipon: siponimod; pone: ponesimod; FTY: FTY720.
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fig3: Balancing the SphK1/S1P rheostat for diabetes and cancer comorbidity treatments. Second generation S1P receptor modulators are currently being developed to target individual and multiple S1P receptors. Each of the receptor modulators binds to individual or multiple receptors to block or activate the S1P receptor. Siponimod is a S1P1,4,5 modulator; ponesimod is an agonist for S1P1,3,4; KRP-203 is an agonist for S1P1,4; ONO-4641 is an agonist for S1P1,4,5; RPC1063 is an agonist for S1P1,4,5; Cs-0777 is an agonist for S1P1,3,5; GSK2018682 is an agonist for S1P1,5. FTY720 and JTE-013 are described in Figure 2. These novel S1P receptors and downstream signalling pathways and functions are reviewed in [88, 93]. Sipon: siponimod; pone: ponesimod; FTY: FTY720.

Mentions: The controversial function of current S1P agonists and functional antagonists has been associated with binding of differing S1P receptor transmembrane expression, such as demonstrated for FTY720. As discussed above, SphK1/S1P inhibitors can have positive and negative impact for diabetic patients depending on the patient's specific condition. Current second generation S1P receptor agonists hold much promise for comorbidity cancer/diabetes treatments and are reviewed in [88, 89]. A comparison of fingolimod (FTY720) and the most advanced next generation S1P modulators (siponimod, ponesimod, KRP-203, ONO-4641, RPC1063, CS-0777, and GSK2018682), each modulator targeting common and different S1P receptors, are illustrated in Figure 3 [88, 93]. Comparative selectivity of S1P modulator activation of specific S1P receptors is shown in Table 1. Knowledge of specific S1P receptor function provides some insight into how S1P receptor modulators may be targeted for comorbidity treatments.


Switching the sphingolipid rheostat in the treatment of diabetes and cancer comorbidity from a problem to an advantage.

Haass NK, Nassif N, McGowan EM - Biomed Res Int (2015)

Balancing the SphK1/S1P rheostat for diabetes and cancer comorbidity treatments. Second generation S1P receptor modulators are currently being developed to target individual and multiple S1P receptors. Each of the receptor modulators binds to individual or multiple receptors to block or activate the S1P receptor. Siponimod is a S1P1,4,5 modulator; ponesimod is an agonist for S1P1,3,4; KRP-203 is an agonist for S1P1,4; ONO-4641 is an agonist for S1P1,4,5; RPC1063 is an agonist for S1P1,4,5; Cs-0777 is an agonist for S1P1,3,5; GSK2018682 is an agonist for S1P1,5. FTY720 and JTE-013 are described in Figure 2. These novel S1P receptors and downstream signalling pathways and functions are reviewed in [88, 93]. Sipon: siponimod; pone: ponesimod; FTY: FTY720.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383402&req=5

fig3: Balancing the SphK1/S1P rheostat for diabetes and cancer comorbidity treatments. Second generation S1P receptor modulators are currently being developed to target individual and multiple S1P receptors. Each of the receptor modulators binds to individual or multiple receptors to block or activate the S1P receptor. Siponimod is a S1P1,4,5 modulator; ponesimod is an agonist for S1P1,3,4; KRP-203 is an agonist for S1P1,4; ONO-4641 is an agonist for S1P1,4,5; RPC1063 is an agonist for S1P1,4,5; Cs-0777 is an agonist for S1P1,3,5; GSK2018682 is an agonist for S1P1,5. FTY720 and JTE-013 are described in Figure 2. These novel S1P receptors and downstream signalling pathways and functions are reviewed in [88, 93]. Sipon: siponimod; pone: ponesimod; FTY: FTY720.
Mentions: The controversial function of current S1P agonists and functional antagonists has been associated with binding of differing S1P receptor transmembrane expression, such as demonstrated for FTY720. As discussed above, SphK1/S1P inhibitors can have positive and negative impact for diabetic patients depending on the patient's specific condition. Current second generation S1P receptor agonists hold much promise for comorbidity cancer/diabetes treatments and are reviewed in [88, 89]. A comparison of fingolimod (FTY720) and the most advanced next generation S1P modulators (siponimod, ponesimod, KRP-203, ONO-4641, RPC1063, CS-0777, and GSK2018682), each modulator targeting common and different S1P receptors, are illustrated in Figure 3 [88, 93]. Comparative selectivity of S1P modulator activation of specific S1P receptors is shown in Table 1. Knowledge of specific S1P receptor function provides some insight into how S1P receptor modulators may be targeted for comorbidity treatments.

Bottom Line: Cancer and diabetes are among the most common diseases in western societies.Epidemiological studies have shown that diabetic patients have a significantly higher risk of developing a number of different types of cancers and that individuals with comorbidity (cancer and diabetes/prediabetes) have a poorer prognosis relative to nondiabetic cancer patients.This paper will highlight some of the complexities inherent in the use of the emerging sphingosine kinase/S1P modulators in the treatment of comorbidity of diabetes and cancer.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia ; The Centenary Institute, Newtown, NSW, Australia ; Discipline of Dermatology, University of Sydney, Camperdown, NSW, Australia.

ABSTRACT
Cancer and diabetes are among the most common diseases in western societies. Epidemiological studies have shown that diabetic patients have a significantly higher risk of developing a number of different types of cancers and that individuals with comorbidity (cancer and diabetes/prediabetes) have a poorer prognosis relative to nondiabetic cancer patients. The increasing frequency of comorbidity of cancer and diabetes mellitus, mainly type 2 diabetes, has driven the development of therapeutic interventions that target both disease states. There is strong evidence to suggest that balancing the sphingolipid rheostat, ceramide--sphingosine--sphingosine-1-phosphate (S1P) is crucial in the prevention of diabetes and cancer and sphingosine kinase/S1P modulators are currently under development for the treatment of cancer and diabetes. This paper will highlight some of the complexities inherent in the use of the emerging sphingosine kinase/S1P modulators in the treatment of comorbidity of diabetes and cancer.

Show MeSH
Related in: MedlinePlus