PPARγ agonists follow an unknown TRAIL in lung cancer

Lipkowitz, Stanley; Dennis, Phillip A.

doi:10.4161/cbt.6.1.3751

Cited by 5 publications

(4 citation statements)

References 37 publications

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“…8,28,29 As recently reported, PPARγ ligands potentiate TRAIL-induced apoptosis in lung cancer cells by downregulating FLIP and upregulating TRAIL-R2. 11,30 Moreover, p53 was suggested to enhance the degradation of FLIP via a ubiquitin/proteasome pathway. 31 At a molecular level, TNFα-and JNK-dependent activation of the E3 ubiquitin ligase Itch was demonstrated to induce the specific ubiquitination of FLIP.…”

Section: Discussionmentioning

confidence: 99%

Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD

Grund¹,

Ahmadi²,

Jung³

et al. 2008

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD

Grund¹,

Ahmadi²,

Jung³

et al. 2008

Cancer Biology & Therapy

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“…99 Clinical trials in prostate, colon, lung, and thyroid cancer also did not find a meaningful benefit of TZD therapy. [100][101][102][103][104][105] In summary, the clinical effects achieved by PPAR␥ agonists have not been resounding and probably do not merit a primary role for them in cancer therapy. However, their low toxicity profile and the observation that they can achieve additive or synergistic effects combined with other anticancer agents such as retinoids, histone deacetylase (HDAC) inhibitors, or TRAIL ligands 86,100-104 make them possible candidates to include in adjuvant or combination therapy trials.…”

Section: Ppar␥ Receptor Ligandsmentioning

confidence: 99%

Differentiation therapy of leukemia: 3 decades of development

Nowak

Stewart

Koeffler

2009

Blood

313

241

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IntroductionA characteristic abnormality of leukemia cells is that they are blocked at an early stage of their development and fail to differentiate into functional mature cells. During the 1970s and 1980s, several scientific achievements popularized the strategy of inducing malignant cells to overcome their block of differentiation and enter the apoptotic pathways as an elegant alternative to killing cancer cells by cytotoxic therapies. This intervention could theoretically limit exposure to unwanted side effects of cytotoxic chemotherapy, and more importantly, improve complete remission and cure rates. Pioneering reports included studies demonstrating the differentiating capability of dimethylsulfoxide (DMSO) on erythropoiesis, 1 efforts to elucidate substances to control the differentiation of myeloid leukemia, 2 and the first evidence of the differentiating properties of retinoic acid. 3,4 The initial promising preclinical results of this approach prompted a review article by us 25 years ago concerning the possibilities and therapeutic implications of differentiation induction in leukemia. 5 At that stage, cell line models for in vitro differentiation experiments were described. Substances such as phorbol diesters, teleocidins, polar planar drugs, cytokines, retinoids, and vitamin D metabolites showed dramatic potential to differentiate cell lines such as HL-60, KG-1, ML-3, or K562 in vitro and fueled the hope of developing a new approach to treat cancers by overcoming their blocked differentiation. Today, 25 years later, we discuss the progress and the clinical achievements of this therapeutic approach. Ligands of nuclear hormone receptorsPoster child of success: complete remissions of APL by differentiation therapyThe potential for differentiating therapy to improve cure rates in leukemia is exemplified by the development of all-trans retinoic acid (ATRA) for the targeted treatment of acute promyelocytic leukemia (APL). One of the most remarkable results of initial in vitro experiments was achieved in differentiating HL-60 cells with ATRA, which produced terminal differentiation in 90% of cells with 10 Ϫ6 M retinoic acid. 3 Investigators soon realized that ATRA was specifically effective in APL cells carrying a typical chromosomal translocation between chromosomes 15 and 17 [t(15;17)(q22; q21)] 6 but not in other leukemias. 4 The first APL patients treated with ATRA in the early 1980s achieved encouraging remissions by the new therapy. [7][8][9][10] The first clinical trial of ATRA reported 16 newly diagnosed, and 8 anthracycline refractory patients who were induced with single-agent ATRA. Complete hematologic remission was induced in all patients; more than 90% of samples from these individuals demonstrated in vitro evidence of blast differentiation. 10 This seminal trial changed the management and prognosis of APL, and introduced a paradigm for success of cell differentiation therapy. Subsequently, APL therapy was improved stepwise through elucidation of the most effective combination regimen of ATRA wit...

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“…PPAR γ ligands sensitize leukemic, lung and endothelial cells to the TRAIL-induced apoptosis by enhancing DR5 expression [99, 100] pointing to possible synergy between PPAR γ agonists and TRAIL therapies.…”

Section: Pparγ Ligands In Combination Treatments: Can We Augment mentioning

confidence: 99%

PPARγ and Agonists against Cancer: Rational Design of Complementation Treatments

2008

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PPARγ is a member of the ligand-activated nuclear receptor superfamily: its ligands act as insulin sensitizers and some are approved for the treatment of metabolic disorders in humans. PPARγ has pleiotropic effects on survival and proliferation of multiple cell types, including cancer cells, and is now subject of intensive preclinical cancer research. Studies of the recent decade highlighted PPARγ role as a potential modulator of angiogenesis in vitro and in vivo. These observations provide an additional facet to the PPARγ image as potential anticancer drug. Currently PPARγ is regarded as an important target for the therapies against angiogenesis-dependent pathological states including cancer and vascular complications of diabetes. Some of the studies, however, identify pro-angiogenic and tumor-promoting effects of PPARγ and its ligands pointing out the need for further studies. Below, we summarize current knowledge of PPARγ regulatory mechanisms and molecular targets, and discuss ways to maximize the beneficial activity of the PPARγ agonists.

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PPARγ agonists follow an unknown TRAIL in lung cancer

Cited by 5 publications

References 37 publications

Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD

Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD

Differentiation therapy of leukemia: 3 decades of development

PPARγ and Agonists against Cancer: Rational Design of Complementation Treatments

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