Revisiting Non-Cancer Drugs for Cancer Therapy

Yang, Eun Ju; Wu, Changjie; Liu, Yifan; Lv, Junfang; Shim, Joong Sup

doi:10.2174/1568026616666160216154441

Cited by 13 publications

(11 citation statements)

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“…These tests were performed on an annual basis at the cell center services facility of the University of Pennsylvania. Cells were grown in RPMI-1640 medium (Gibco) containing 10% fetal bovine serum (Cellgro) and maintained in 150 cm 3 culture flasks (Corning) in a humidified atmosphere of 95% air and 5% CO 2 . Cells were harvested using 0.02% tetrasodium EDTA in PBS.…”

Section: Cell Linesmentioning

confidence: 99%

“…Many approaches are currently being developed including immunotherapy, gene therapy, combination and repositioning therapy. 3,4 Another approach is the enhanced delivery of drugs to solid tumors using nanoparticulate drug carriers. Nanoparticles selectively accumulate in solid tumors due to their ability to extravasate through the capillary discontinuities generated by tumor angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Nanomicellar Lenalidomide–Fenretinide Combination Suppresses Tumor Growth in an MYCN Amplified Neuroblastoma Tumor

Orienti

Farruggia

Nguyen

et al. 2020

IJN

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In a previous study, we demonstrated that the combination of fenretinide with lenalidomide, administered by a novel nanomicellar formulation (FLM), provided a strong antitumor effect in a neuroblastoma TrkB-expressing tumor. In this study, we tested the nanomicellar combination in an MYCN amplified neuroblastoma xenograft to assess its efficacy in different tumor genotypes and evaluate the interactions of the nanomicelles with the tumor cells. Experimental Design: FLM was administered to mice bearing human NLF xenografts to evaluate its efficacy in comparison with the nanomicelles containing fenretinide alone (FM). Confocal laser-scanning fluorescence microscopy images of the NLF cells treated with FLM and FM allowed us to estimate the nanomicelle ability to transport the encapsulated drugs inside the tumor cells. Flow cytometric analysis of the cells from treated tumors was performed to assess the effect of treatment on GD2 expression and NK cell infiltration. Results: FLM and FM decreased the growth of NLF xenografts at comparable extents during the treatment period. Afterwards, FLM induced a progressive tumor regression without regrowth, while FM treatment was followed by regrowth within 15-20 days after the end of treatment. Both FLM and FM were able to penetrate the tumor cells transporting the encapsulated drugs. FLM transported higher amount of fenretinide inside the cells. Also, FLM treatment strongly increased GD2 expression in treated tumors and slightly decreased the NK infiltration compared to FM. Conclusion: FLM treatment induced a superior antitumor response than FM in NLF xenografts, presumably due to the combined effects of fenretinide cytotoxicity and lenalidomide antiangiogenic activity. The ability of FLM to penetrate tumor cells, transporting the encapsulated drugs, substantially improved the therapeutic efficiency of this system. Moreover, the enhancement of GD2 expression in FLM treated tumors offers the possibility to further increase the antitumor effect by the use of anti-GD2 CART cells and anti-GD2 antibodies in combination with FLM in multimodal therapies.

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Section: Cell Linesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nanomicellar Lenalidomide–Fenretinide Combination Suppresses Tumor Growth in an MYCN Amplified Neuroblastoma Tumor

Orienti

Farruggia

Nguyen

et al. 2020

IJN

View full text Add to dashboard Cite

show abstract

“…These tests were performed on an annual basis at the cell center services facility of the University of Pennsylvania. Cells were grown in RPMI-1640 medium (Gibco) containing 10% fetal bovine serum (Cellgro) and maintained in 150 cm 3 culture flasks (Corning) in a humidified atmosphere of 95% air and 5% CO 2 . Transfected cells were maintained in media containing 0.3 mg/mL G418 sulfate (stock solution: 20 mg/mL; Corning).…”

Section: Cell Linesmentioning

confidence: 99%

“…Many approaches are currently being developed, including immunotherapy, gene therapy, synergistic combinations and repurposing therapy. 3 Another approach is the enhanced drug delivery to solid tumors using nanoparticles as carriers of active agents. Indeed, nanoparticles selectively accumulate in solid tumors based on their size, which allows extravasation through the leaky tumor vasculature that characterizes rapidly growing tumors.…”

Section: Introductionmentioning

confidence: 99%

A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model

Orienti¹,

Nguyen²,

Guan³

et al. 2019

DDDT

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Purpose: Currently >50% of high-risk neuroblastoma (NB) patients, despite intensive therapy and initial partial or complete response, develop recurrent NB due to the persistence of minimal residual disease (MRD) that is resistant to conventional antitumor drugs. Indeed, their low therapeutic index prevents drug-dose escalation and protracted administration schedules, as would be required for MRD treatment. Thus, more effective and less toxic therapies are urgently needed for the management of MRD. To address this aim, we evaluated a new combination of fenretinide and lenalidomide, both endowed with antitumor activity and low-toxicity profiles. New nanomicelles were prepared as carriers for this combination to maximize bioavailability and accumulation at the tumor site because of the enhanced permeability and retention (EPR) effect. Experimental design: New nanomicelles containing the fenretinide-lenalidomide combination (FLnMs) were prepared by a one-step method, providing high drug encapsulation and micelle dimensions suitable for tumor accumulation. Their administration to mice bearing human NB xenografts allowed us to evaluate their efficacy in comparison with the nanomicelles containing fenretinide alone (FnMs). Results: Treatment by FLnMs significantly decreased the tumor growth of NB xenografts. FLnMs were more active than FnMs despite comparable fenretinide concentrations in tumors, and lenalidomide alone did not show cytotoxic activity in vitro against NB cells. The tumor mass at the end of treatment with FLnMs was predominantly necrotic, with a decreased Ki-67 proliferation index. Conclusion: FLnMs provided superior antitumor efficacy in NB xenografts compared to FnMs. The enhanced efficacy of the combination was likely due to the antiangiogenic effect of lenalidomide added to the cytotoxic effect of fenretinide. This new nanomicellar combination is characterized by a low-toxicity profile and offers a novel therapeutic option for the treatment of high-risk tumors where the persistence of MRD requires repeated administrations of therapeutic agents over long periods of time to avoid recurrent disease.

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“…The advantage of such approaches is that they mitigate drug resistance markedly and escalated therapeutic effect is achieved even under low-dose combinations [77][78][79]. Thus, it is quite obvious that conjugated therapies may vanquish dose-limiting toxicity, a major issue in pharmacological intervention [80]. Epigenetically based combinatorial strategies have been tested against MLL-rearranged leukemias [81].…”

Section: Strategy 4: Hdot1l Inhibitors In Combinatorial Therapymentioning

confidence: 99%

Therapeutic strategies against hDOT1L as a potential drug target in MLL-rearranged leukemias

et al. 2020

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Therapeutic intervention of proteins participating in chromatin-mediated signaling with small-molecules is a novel option to reprogram expression networks for restraining disease states. Protein methyltransferases form the prominent family of such proteins regulating gene expression via epigenetic mechanisms thereby representing novel targets for pharmacological intervention. Disruptor of telomeric silencing, hDot1L is the only non-SET domain containing histone methyltransferase that methylates histone H3 at lysine 79. H3K79 methylation mediated by hDot1L plays a crucial role in mixed lineage leukemia (MLL) pathosis. MLL fusion protein mediated mistargeting of DOT1L to aberrant gene locations results in ectopic H3K79 methylation culminating in aberrant expression of leukemogenic genes like HOXA9 and MEIS1. hDOT1L has thus been proposed as a potential target for therapeutic intervention in MLL. This review presents the general overview of hDOT1L and its functional role in distinct biological processes. Furthermore, we discuss various therapeutic strategies against hDOT1L as a promising drug target to vanquish therapeutically challenging MLL.

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Revisiting Non-Cancer Drugs for Cancer Therapy

Cited by 13 publications

References 0 publications

<p>Nanomicellar Lenalidomide–Fenretinide Combination Suppresses Tumor Growth in an <em>MYCN</em> Amplified Neuroblastoma Tumor</p>

<p>Nanomicellar Lenalidomide–Fenretinide Combination Suppresses Tumor Growth in an <em>MYCN</em> Amplified Neuroblastoma Tumor</p>

<p>A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model</p>

Therapeutic strategies against hDOT1L as a potential drug target in MLL-rearranged leukemias

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