Nanoacetylated N-(4-Hydroxyphenyl) Retinamide Modulates Histone Acetylation–Methylation Epigenetic Disparity to Restrict Epithelial–Mesenchymal Transition in Neuroblastoma

Article

作者: Sharma, Angela ; Karmakar, Surajit ; Sardoiwala, Mohammed Nadim ; Choudhury, Subhasree Roy ; Dev, Atul ; MohanBhai, Soni Jignesh

Neuroblastoma (NB) is an extracranial pediatric tumor with highly invasive growth of cancer biomass and frequent metastases. During the differentiation process in embryonic development, altered epigenetic modifications lead to dysregulated expression of pluripotency markers, resulting in epithelial-mesenchymal transition (EMT) progression. Currently, available chemotherapies have provided a limited solution to this problem due to systemic toxicities and drug resistance. Epigenetic therapeutic molecules like histone deacetylase inhibitors are still in the initial stages of development. We have developed a retinoid (N-(4-hydroxyphenyl) retinamide, 4HPR) loaded acetylated human serum albumin (HSA) nanoformulation to address the epigenetic imbalance and chemoresistance in NB. The idea was conceived to deliver an acetyl pool along with a chemotherapeutic drug, 4HPR, to restrict the invasiveness of NB by maintaining the balance between histone acetylation and trimethylation. The therapeutic efficacy of the formulation was successfully evaluated in the in vitro and in vivo xenograft mouse model system of neuroblastoma. The synthesized nanoparticles show high biocompatibility and therapeutic efficacy in treating neuroblastoma subcutaneous xenografts in nude mice.

2020-10-01·Current Medical Science4区 · 医学

4-Hydroxyphenyl Retinamide Preferentially Targets FLT3 Mutated Acute Myeloid Leukemia via ROS Induction and NF-κB Inhibition

4区 · 医学

Article

作者: Zhang, Hui ; Xu, Hao-Yu ; Qiu, Fei ; Wei, Feng-Gui ; Ye, Qian ; Zhao, Xin-Ying ; Zhang, Ran-Ran

FMS-like tyrosine kinase 3 (FLT3) mutation is strongly associated with poor prognosis in acute myeloid leukemia (AML). Though many FLT3 inhibitors have been developed for clinical application with 34%-56% complete remission rate, patients would develop resistance sooner or later after initial response to tyrosine kinase inhibitors (TKIs), such as gilteritinib. And increasing studies have shown that several resistance related mutations of FLT3 emerged during the AML progression. Thus, further investigation is warranted for these FLT3^mut AML patients to achieve a better treatment outcome. 4-Hydroxyphenyl retinamide (4-HPR) has been investigated extensively in animal models and clinical trials as an anticancer/chemopreventive agent and is currently used for protection against cancer development/recurrence, with minimal side effects. In this study, we performed gene-set enrichment analysis and found that down-regulated genes induced by 4-HPR were associated with FLT3-ITD gene sets. CD34⁺ AML stem/progenitor cells separated from 32 AML samples were treated with 4-HPR. Correlation analysis showed that AML cells with FLT3-ITD genetic alteration were more sensitive to 4-HPR treatment than those without FLT3-ITD. Next, we treated 22 primary AML cells with 4-HPR and found that 4-HPR was more toxic to AML cells with FLT3-ITD. These results indicated that 4-HPR was preferentially cytotoxic to all FLT3-ITD AML⁺ cells irrespective of stem/progenitor cells or blast cells. 4-HPR-induced reactive oxygen species (ROS) production and NF-κB inhibition might be the reason of 4-HPR selectivity on FLT3 mutated AML cells.

2011-01-01·World Journal of Oncology

N-(4-Hydroxyphenyl) Retinamide Potentiated Anti-Tumor Efficacy of Genistein in Human Ewing’s Sarcoma Xenografts

Article

作者: Naren L. Banik ; Swapan K. Ray ; Surajit Karmakar ; Subhasree Roy Choudhury

BACKGROUND: Ewing's sarcoma is a pediatric tumor that mainly occurs in soft tissues and bones. New therapeutic strategies are urgently needed for treatment of Ewing's sarcoma. We examined for the first time the efficacy of N-(4-hydroxyphenyl) retinamide (4-HPR) and genistein (GST) alone and also in combination for controlling growth of human Ewing's sarcoma SK-N-MC and RD-ES xenografts. METHODS: Efficacy of combination therapy was evaluated using histopathological parameters. Molecular mechanisms of combination therapy were detected using Western blotting and immunofluorescence microscopy. RESULTS: Histopathological examination of tumor sections showed that control group maintained characteristic growth of tumors, 4-HPR alone caused differentiation of tumor cells, GST alone induced apoptosis to some extent, and combination of 4-HPR and GST significantly induced apoptosis in both Ewing's sarcoma xenografts. Time-dependent reductions in body weight, tumor volume, and tumor weight were also found. Combination therapy increased Bax:Bcl-2 ratio to trigger mitochondrial release of Smac/Diablo into the cytosol to down regulate the baculovirus inhibitor-of-apoptosis repeat containing (BIRC) proteins such as BIRC-2 and BIRC-3 and thereby promote apoptosis. Activation of caspase-3 and mitochondrial release of apoptosis-inducing factor (AIF) occurred in course of apoptosis. Down regulation of the survival factor NF-κB and the angiogenic factors VEGF and FGF2 and increase in caspase-3 activity controlled tumor growth. In situ immunofluorescent labelings showed overexpression of calpain, caspase-12, and caspase-3, and AIF in xenografts, indicating induction of cysteine proteases and AIF for apoptosis. CONCLUSIONS: Results revealed that combination of 4-HPR and GST could be highly effective treatment for inhibiting Ewing's sarcomas in vivo.

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适应症	国家/地区	公司	日期
白血病前期	中国	中国医学科学院	1999-06-03

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适应症	最高研发状态	国家/地区	公司	日期
骨髓增生异常综合征	临床3期	-	BASF SE	-
骨髓增生异常综合征	临床3期	-	Supergen Bioenergy Hub	-
骨髓增生异常综合征	临床3期	-	中国医学科学院	-
白血病前期	临床3期	美国	-	-