Repurposing antitubercular agent isoniazid for treatment of prostate cancer

Lv, Qingzhi; Wang, Dun; Yang, Zhiman; Yang, Jincheng; Zhang, Ruoshi; Yang, Xiaoguang; Wang, Menglin; Wang, Yongjun

doi:10.1039/c8bm01189c

Cited by 17 publications

(21 citation statements)

References 33 publications

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“…We recently demonstrated that radiolabeled cyanine dye molecules can be used to detect and diagnose cancer lesions [24,25]. Additional reports of cancer cell-specific delivery and targeting of drug-cyanine dye conjugates to tumors have been described by us and other laboratories [26,27,28,29,30,31,32]. Considering ongoing research on genistein in our laboratory [33], we sought to improve its therapeutic potential by conjugating it with a cyanine dye.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Genistein-IR783 Conjugate: Cancer Cell Targeted Delivery in MCF-7 for Superior Anti-Cancer Therapy

et al. 2019

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The flavonoid-based natural product genistein is a biologically active compound possessing promising anti-oxidant and anti-cancer properties. Poor pharmacokinetics along with low potency limit however the therapeutic application of genistein in cancer therapy. In order to overcome those limitations and to expand its therapeutic window of efficacy, we sought to covalently attach genistein with a heptamethine cyanine dye—IR 783—for cancer cell targeting and enhanced delivery to tumors. Herein we report the synthesis, a selective detailed characterization and preliminary in vitro/in vivo biological evaluation of genistein-IR 783 conjugate 4. The conjugate 4 displayed improved potency against human breast cancer MCF-7 cells (10.4 ± 1.0 μM) as compared with the parent genistein (24.8 ± 0.5 μM) or IR 783 (25.7 ± 0.7 μM) and exhibited selective high uptake in MCF-7 as against the normal mammary gland MCF-10A cells in various assays. In the cell viability assay, conjugate 4 exhibited over threefold lower potency against MCF-10A cells (32.1 ± 1.1 μM) suggesting that the anti-cancer profile of parent genistein is significantly improved upon conjugation with the dye IR783. Furthermore, the genistein-IR783 conjugate 4 was shown to be especially accumulated in MCF-7 cancer cells by fluorescent intensity measurements and inverted fluorescence microscopy in fixed cells as well as in live cells with time via live cell confocal fluorescence imaging. The mechanism-based uptake inhibition of conjugate 4 was observed with OATPs inhibitor BSP and in part with amiloride, as a macropinocytosis inhibitor. For the first time we have shown amiloride inhibited uptake of cyanine dye by about ~40%. Finally, genistein-IR 783 conjugate 4 was shown to be localized in MCF-7 tumor xenografts of mice breast cancer model via in vivo near infrared fluorescence (NIRF) imaging. In conclusion, conjugation of genistein with cyanine dye IR783 indeed improved its pharmacological profile by cancer cell selective uptake and targeting and therefore warrants further investigations as a new anti-cancer therapeutics derived from natural product genistein.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Genistein-IR783 Conjugate: Cancer Cell Targeted Delivery in MCF-7 for Superior Anti-Cancer Therapy

et al. 2019

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“…MAOA is a mitochondrial-bound enzyme. It was confirmed that MAOA may promote the progression of prostate cancer by mediating EMT (Wu et al, 2014;Lv et al, 2018). However, because conflicting results have been reported for the importance of MAOA in HCC and cholangiocarcinoma (Huang et al, 2012;Li et al, 2014), the role of MAOA may vary across cancer types.…”

Section: Discussionmentioning

confidence: 93%

Integrating Genome-Wide Association Studies and Gene Expression Profiles With Chemical-Genes Interaction Networks to Identify Chemicals Associated With Colorectal Cancer

et al. 2020

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Colorectal cancer (CRC) is the third most common cancer and has the second highest mortality rate in global cancer. Exploring the associations between chemicals and CRC has great significance in prophylaxis and therapy of tumor diseases. This study aims to explore the relationships between CRC and environmental chemicals on genetic basis by bioinformatics analysis. The genome-wide association study (GWAS) datasets for CRC were obtained from the UK Biobank. The GWAS data for colon cancer (category C18) includes 2,581 individuals and 449,683 controls, while that of rectal cancer (category C20) includes 1,244 individuals and 451,020 controls. In addition, we derived CRC gene expression datasets from the NCBI-GEO (GSE106582). The chemicals related gene sets were acquired from the comparative toxicogenomics database (CTD). Transcriptome-wide association study (TWAS) analysis was applied to CRC GWAS summary data and calculated the expression association testing statistics by FUSION software. We performed chemicals related gene set enrichment analysis (GSEA) by integrating GWAS summary data, mRNA expression profiles of CRC and the CTD chemical-gene interaction networks to identify relationships between chemicals and genes of CRC. We observed several significant correlations between chemicals and CRC. Meanwhile, we also detected 5 common chemicals between colon and rectal cancer, including methylnitronitrosoguanidine, isoniazid, PD 0325901, sulindac sulfide, and importazole. Our study performed TWAS and GSEA analysis, linked prior knowledge to newly generated data and thereby helped identifying chemicals related to tumor genes, which provides new clues for revealing the associations between environmental chemicals and cancer.

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“…The direct translation of MAOA inhibitor into cancer therapy is impracticable due to its extensive action on central nervous system. A tumor-targeting cyanine dye, MHI-148, was shown to conjugate with two irreversible MAOA inhibitors, i.e., clorgyline ( 38 ) [ 83 ] and isoniazid ( 39 ) [ 84 ], and enhanced their selectivity ( Fig. 10 D).…”

Section: Targeted Therapymentioning

confidence: 99%

Cyanine conjugates in cancer theranostics

Yang

Zhou

Yue

et al. 2021

Bioactive Materials

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Cyanine is a meritorious fluorogenic core for the construction of fluorescent probes and its phototherapeutic potential has been enthusiastically explored as well. Alternatively, the covalent conjugation of cyanine with other potent therapeutic agents not only boosts its therapeutic efficacy but also broadens its therapeutic modality. Herein, we summarize miscellaneous cyanine–therapeutic agent conjugates in cancer theranostics from literature published between 2014 and 2020. The application scenarios of such theranostic cyanine conjugates covered common cancer therapeutic modalities, including chemotherapy, phototherapy and targeted therapy. Besides, cyanine conjugates that serve as nanocarriers for drug delivery are introduced as well. In an additional section, we analyze the potential of these conjugates for clinical translation. Overall, this review is aimed to stimulate research interest in exploring unattempted therapeutic agents and novel conjugation strategies and hopefully, accelerate clinical translation in this field.

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Repurposing antitubercular agent isoniazid for treatment of prostate cancer

Abstract: Development of isoniazid–dye conjugates as versatile antitumor agents for mitochondria-targeting, NIR imaging and potent antitumor efficacy.

Cited by 17 publications

References 33 publications

Synthesis and Biological Evaluation of Genistein-IR783 Conjugate: Cancer Cell Targeted Delivery in MCF-7 for Superior Anti-Cancer Therapy

Synthesis and Biological Evaluation of Genistein-IR783 Conjugate: Cancer Cell Targeted Delivery in MCF-7 for Superior Anti-Cancer Therapy

Integrating Genome-Wide Association Studies and Gene Expression Profiles With Chemical-Genes Interaction Networks to Identify Chemicals Associated With Colorectal Cancer

Cyanine conjugates in cancer theranostics

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