Adrenocortical Hormone in Arthritis : Preliminary Report

Hench, Philip S.; Kendall, Edward C.; Slocumb, Charles H.; Polley, Howard F.

doi:10.1136/ard.8.2.97

Cited by 210 publications

(71 citation statements)

References 10 publications

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“…Knowledge of how GCs exert their therapeutic effects is surprisingly incomplete, considering their long clinical history. 4 A better understanding of the mechanism of action and nature of resistance is needed to improve the efficacy of GC therapy in CLL patients.…”

Section: Introductionmentioning

confidence: 99%

PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia

Tung

Shi

Wong

et al. 2013

Blood

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Key Points• Glucocorticoids downregulate PKM2 and metabolism in CLL cells, impairing access to bioenergetic programs needed to repair cell damage.• PPARa and fatty acid oxidation antagonists potentiate the cytotoxic effects of glucocorticoids.High-dose glucocorticoids (GCs) can be a useful treatment for aggressive forms of chronic lymphocytic leukemia (CLL). However, their mechanism of action is not well understood, and resistance to GCs is inevitable. In a minimal, serum-free culture system, the synthetic GC dexamethasone (DEX) was found to decrease the metabolic activity of CLL cells, indicated by down-regulation of pyruvate kinase M2 (PKM2) expression and activity, decreased levels of pyruvate and its metabolites, and loss of mitochondrial membrane potential. This metabolic restriction was associated with decreased size and death of some of the tumor cells in the population. Concomitant plasma membrane damage increased killing of CLL cells by DEX. However, the nuclear receptor peroxisome proliferator activated receptor a (PPARa), which regulates fatty acid oxidation, was also increased by DEX, and adipocyte-derived lipids, lipoproteins, and propionic acid protected CLL cells from DEX. PPARa and fatty acid oxidation enzyme inhibitors increased DEX-mediated killing of CLL cells in vitro and clearance of CLL xenografts in vivo. These findings suggest that GCs prevent tumor cells from generating the energy needed to repair membrane damage, fatty acid oxidation is a mechanism of resistance to GC-mediated cytotoxicity, and PPARa inhibition is a strategy to improve the therapeutic efficacy of GCs. (Blood. 2013;122(6):969-980)

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Section: Introductionmentioning

confidence: 99%

PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia

Tung

Shi

Wong

et al. 2013

Blood

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“…Özellikle etyopatogeneze yönelik olan bu geliflmeler daha etkili ve modern tedavi yöntemleri-nin de önünü açm›flt›r. Ancak bu grup hastal›klar›n tedavisindeki esas dönüm noktas› di¤er pek çok hastal›kta oldu¤u gibi 1940'l› y›llar›n sonunda kortikosteroidlerin keflfi olmufltur 5 . Deri hastal›klar›nda özellikle de OBH'lerde 1960'l› y›llar›n bafl›ndan itibaren kullan›lmaya bafllanan kortikosteroidler sayesinde nerdeyse bir mucize gerçekleflmifl ve örne¤in %90'a varan mortalite ile grubun en fatal hastal›¤› olan pemfigus vulgariste bile bu oran k›sa sürede %30'a kadar indirilmifltir.…”

Section: Resultsunclassified

Autoimmune Bullous Diseases

Uzun¹

2011

TURKDERM

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“…In 1950, subsequent to the brilliant discovery by Hench, Kendall, Slocumb, and Polley (1949), at the Mayo Clinic, on the usefulness of corti'sone and A.C.T.H. in arthritis, our earlier studies on this problem were resumed.…”

Section: Necrosinmentioning

confidence: 99%

Biochemical Mechanisms in Inflammation

1956

JAMA

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Adrenocortical Hormone in Arthritis : Preliminary Report

Cited by 210 publications

References 10 publications

PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia

PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia

Autoimmune Bullous Diseases

Biochemical Mechanisms in Inflammation

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