Pegylated Wortmannin and 17-Hydroxywortmannin Conjugates as Phosphoinositide 3-Kinase Inhibitors Active in Human Tumor Xenograft Models

Zhu, Tianmin; Gu, Jinjie; Yu, Ker; Lucas, Judy; Cai, Ping; Tsao, Rushung; Gong, Yumin; Li, Fangbiao; Chaudhary, Inder; Desai, Pankaja; Ruppen, Mark E.; Fawzi, Mahdi B.; Gibbons, James J.; Ayral‐Kaloustian, Semiramis; Skotnicki, Jerauld S.; Mansour, Tarek S.; Zask, Arie

doi:10.1021/jm050901o

Cited by 41 publications

(28 citation statements)

References 14 publications

(42 reference statements)

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“…The self-activating viridin prodrug undergoes slow self activation to release low and sustained levels of NBD-wortmannin (48, 49), increasing its potency. Wortmannin is a potent inhibitor of PI3K and other kinases (50)(51)(52)(53). Therefore, in light of the beneficial effects of PI3K inhibitors in models of inflammatory disorders (54), we tested the self-activating viridin prodrug directly in vivo, as we had done with dexamethasone.…”

Section: Resultsmentioning

confidence: 99%

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation

Cortez-Retamozo¹,

Świrski²,

Waterman³

et al. 2008

J. Clin. Invest.

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Eosinophils are multifunctional leukocytes that degrade and remodel tissue extracellular matrix through production of proteolytic enzymes, release of proinflammatory factors to initiate and propagate inflammatory responses, and direct activation of mucus secretion and smooth muscle cell constriction. Thus, eosinophils are central effector cells during allergic airway inflammation and an important clinical therapeutic target. Here we describe the use of an injectable MMP-targeted optical sensor that specifically and quantitatively resolves eosinophil activity in the lungs of mice with experimental allergic airway inflammation. Through the use of real-time molecular imaging methods, we report the visualization of eosinophil responses in vivo and at different scales. Eosinophil responses were seen at single-cell resolution in conducting airways using nearinfrared fluorescence fiberoptic bronchoscopy, in lung parenchyma using intravital microscopy, and in the whole body using fluorescence-mediated molecular tomography. Using these real-time imaging methods, we confirmed the immunosuppressive effects of the glucocorticoid drug dexamethasone in the mouse model of allergic airway inflammation and identified a viridin-derived prodrug that potently inhibited the accumulation and enzyme activity of eosinophils in the lungs. The combination of sensitive enzyme-targeted sensors with noninvasive molecular imaging approaches permitted evaluation of airway inflammation severity and was used as a model to rapidly screen for new drug effects. Both fluorescence-mediated tomography and fiberoptic bronchoscopy techniques have the potential to be translated into the clinic.

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Section: Resultsmentioning

confidence: 99%

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation

Cortez-Retamozo¹,

Świrski²,

Waterman³

et al. 2008

J. Clin. Invest.

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“…Although preclinical studies showed Wtmn was an extremely effective radiosensitizer, its clinical translation was limited by poor solubility, low stability, and high toxicity (3)(4)(5)(6)(7)(8). Since its discovery more than four decades ago, many Wtmn analogs have been developed to improve on the stability and pharmacologic properties of Wtmn (9)(10)(11). Today, only one Wtmn analog, PX-866, remains under clinical investigation (12).…”

mentioning

confidence: 99%

Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery

Karve

Werner

Sukumar

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

131

107

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One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3′ kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.nanotechnology | nanoparticle radiosensitizer N anoparticles (NPs) possess unique properties, such as preferential accumulation in tumors and reduced distribution in normal tissue, that make them ideally suited for the treatment of cancer. Consequently, there has been high interest in developing NP-based therapeutics for cancer treatment (1). Current research has been focused on developing NP formulations of widely used chemotherapeutics or newly discovered cancer agents, which are few in number (2). However, one of the promises and great potentials of NP drug-delivery carriers is the reformulation of abandoned cancer therapeutics that were initially promising but failed clinical development due to challenges in delivery. Although these challenges are difficult to overcome with traditional drugdelivery techniques, NP drug-delivery vehicles present an unprecedented opportunity. In this study, we aim to demonstrate proof of principle that NPs permit the reformulation of abandoned therapeutics into formulations appropriate for clinical use.We used wortmannin (Wtmn) as a model drug for our study. Wtmn is a furanosteroid metabolite of the fungi Penicillium funiculosum and Talaromyces (Penicillium) wortmannii (3). It is an inhibitor of phosphatidylinositol 3′ kinases (PI3Ks) and phosphatidylinositol 3′ kinase-related kinases (PIKKs) such as DNAdependent protein kinase (DNA-PK) (4). Although preclinical studies showed Wtmn was an extremely effective radiosensitizer, its clinical translation was limited by poor solubility, low stability, and high toxicity (3-8). Since its discovery more than four decades ago, many Wtmn analogs hav...

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“…Various modifications and conjugations with wortmannin have been reported, establishing it as an effective antitumor agent. 16,27 However, in the present study, the direct apoptotic effect of wortmannin at various concentrations was investigated selectively in the MCF-7 cell line. Thus, the primary goal of these experiments was to determine the apoptotic effects of wortmannin in a widely used MCF-7 cell model.…”

Section: Introductionmentioning

confidence: 95%

“…Furthermore, mutated PI3K activation is abnormally expressed or overexpressed in several cancers, including stomach, colon, breast, lung, ovarian, and pancreatic cancer, with activation of its main downstream gene, Akt. 11,16,17 A study has concluded that PI3K-Akt plays a major role in this cell line with regard to increased drug resistance. 18,19 Deregulated PI3K-Akt activity has also been reported in breast malignancies associated with increased resistance to multiple chemotherapeutics and radiotherapies.…”

Section: Introductionmentioning

confidence: 99%

Wortmannin induces MCF-7 breast cancer cell death via the apoptotic pathway, involving chromatin condensation, generation of reactive oxygen species, and membrane blebbing

Akter¹,

Hossain²,

Kleve³

et al. 2012

BCTT

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Background: Apoptosis can be used as a reliable marker for evaluating potential chemotherapeutic agents. Because wortmannin is a microbial steroidal metabolite, it specifically inhibits the phosphatidyl inositol 3-kinase pathway, and could be used as a promising apoptosis-based therapeutic agent in the treatment of cancer. The objective of this study was to investigate the biomolecular mechanisms involved in wortmannin-induced cell death of breast cancer-derived MCF-7 cells. Methods and results: Our experimental results demonstrate that wortmannin has strong apoptotic effects through a combination of different actions, including reduction of cell viability in a dose-dependent manner, inhibition of proliferation, and enhanced generation of intracellular reactive oxygen species. Conclusion: Our findings suggest that wortmannin induces MCF-7 cell death via a programmed pathway showing chromatin condensation, nuclear fragmentation, reactive oxygen species, and membrane blebbing, which are characteristics typical of apoptosis.

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Pegylated Wortmannin and 17-Hydroxywortmannin Conjugates as Phosphoinositide 3-Kinase Inhibitors Active in Human Tumor Xenograft Models

Cited by 41 publications

References 14 publications

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation

Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery

Wortmannin induces MCF-7 breast cancer cell death via the apoptotic pathway, involving chromatin condensation, generation of reactive oxygen species, and membrane blebbing

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