Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest

Zhao, Yong; Tu, Mei Juan; Wang, Wei Peng; Qiu, Jing; Yu, Ai Xi; Yu, Aiming

doi:10.1038/srep26611

Cited by 38 publications

(55 citation statements)

References 50 publications

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“…Bioengineered miR-34a has showed to decrease the expression of c-Met and inhibited OS cell growth and invasion by inducing apoptosis and cell cycle arrest. This study confirmed the effectiveness and safety of bioengineered miR-34a using an orthotopic OS xenograft tumor mouse model (Zhao et al, 2016). Another study showed an inverse relationship between the expression of miR-34a-5p and c-Met in bone metastasis, but not in non-metastatic or metastatic breast carcinomas (Maroni et al, 2017).…”

Section: Mirna-34 Family and C-metsupporting

confidence: 74%

MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers

Zhan

Zhang

et al. 2020

Front. Cell Dev. Biol.

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MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are components of many signaling pathways associated with tumor aggressiveness and cancer metastasis. Some lncRNAs are classified as competitive endogenous RNAs (ceRNAs) that bind to specific miRNAs to prevent interaction with target mRNAs. Studies have shown that the hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-Met) pathway is involved in physiological and pathological processes such as cell growth, angiogenesis, and embryogenesis. Overexpression of c-Met can lead to sustained activation of downstream signals, resulting in carcinogenesis, metastasis, and resistance to targeted therapies. In this review, we evaluated the effects of anti-oncogenic and oncogenic non-coding RNAs (ncRNAs) on c-Met, and the interactions among lncRNAs, miRNAs, and c-Met in cancer using clinical and tissue chromatin immunoprecipition (ChIP) analysis data. We summarized current knowledge of the mechanisms and effects of the lncRNAs/miR-34a/c-Met axis in various tumor types, and evaluated the potential therapeutic value of lncRNAs and/or miRNAs targeted to c-Met on drug-resistance. Furthermore, we discussed the functions of lncRNAs and miRNAs in c-Met-related carcinogenesis and potential therapeutic strategies.

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Section: Mirna-34 Family and C-metsupporting

confidence: 74%

MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers

Zhan

Zhang

et al. 2020

Front. Cell Dev. Biol.

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“…Likewise, systemic delivery of an improved miR-34a-5p prodrug significantly decreased metastatic lung xenograft tumor growth in mice (Ho et al, 2018). In addition, other formulation of miR-34a prodrugs have resulted in similar findings in orthotopic osteosarcoma xenograft tumor mouse model (Zhao et al, 2016) and in combination therapy to reduce pulmonary metastases and osteosarcoma progression (Jian et al, 2017). In both these studies, it was also shown that the therapeutic doses of mir-34a prodrug were well-tolerated as indicated in blood chemistry profiles monitoring for hepatic and renal toxicities.…”

Section: Berasmentioning

confidence: 85%

Transcription and Translation Inhibitors in Cancer Treatment

et al. 2020

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Transcription and translation are fundamental cellular processes that govern the protein production of cells. These processes are generally up regulated in cancer cells, to maintain the enhanced metabolism and proliferative state of these cells. As such cancerous cells can be susceptible to transcription and translation inhibitors. There are numerous druggable proteins involved in transcription and translation which make lucrative targets for cancer drug development. In addition to proteins, recent years have shown that the "undruggable" transcription factors and RNA molecules can also be targeted to hamper the transcription or translation in cancer. In this review, we summarize the properties and function of the transcription and translation inhibitors that have been tested and developed, focusing on the advances of the last 5 years. To complement this, we also discuss some of the recent advances in targeting oncogenes tightly controlling transcription including transcription factors and KRAS. In addition to natural and synthetic compounds, we review DNA and RNA based approaches to develop cancer drugs. Finally, we conclude with the outlook to the future of the development of transcription and translation inhibitors.

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“…Because some miRNAs regulate genes underlying drug metabolism and disposition (Yu, 2009;Ingelman-Sundberg et al, 2013;Yokoi and Nakajima, 2013;Yu et al, 2016), it is essential to evaluate possible DDIs in vivo for safety reasons. Recently, our group engineered a biologic miR-34a prodrug whose mechanistic actions on target gene expression and xenograft tumor progression have been documented Zhao et al, 2015Zhao et al, , 2016. In this study, we elucidated the effects of biologic miR-34a on the PK of five P450 probe drugs after we established and validated a general, rapid, and practical single-mouse PK approach.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, miR-34a agents may be reintroduced into tumor cells to control tumor progression and metastasis. Recently, our group bioengineered a chimeric miR-34a agent and demonstrated that this biologic miR-34a prodrug is effective to suppress miR-34a target gene expression, inhibit human carcinoma cell proliferation and invasion, and reduce tumor growth in subcutaneous and orthotopic xenograft mouse models Zhao et al, 2015Zhao et al, , 2016. However, it is unknown whether therapeutic miR-34a would cause significant drugdrug interactions (DDIs), which are a critical component in drug development, particularly for combination therapy.…”

Section: Introductionmentioning

confidence: 99%

Effects of MicroRNA-34a on the Pharmacokinetics of Cytochrome P450 Probe Drugs in Mice

Jilek

2017

Drug Metab Dispos

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MicroRNAs (miRNAs or miRs), including miR-34a, have been shown to regulate nuclear receptor, drug-metabolizing enzyme, and transporter gene expression in various cell model systems. However, to what degree miRNAs affect pharmacokinetics (PK) at the systemic level remains unknown. In addition, miR-34a replacement therapy represents a new cancer treatment strategy, although it is unknown whether miR-34a therapeutic agents could elicit any drug-drug interactions. To address this question, we refined a practical single-mouse PK approach and investigated the effects of a bioengineered miR-34a agent on the PK of several cytochrome P450 probe drugs (midazolam, dextromethorphan, phenacetin, diclofenac, and chlorzoxazone) administered as a cocktail. This approach involves manual serial blood microsampling from a single mouse and requires a sensitive liquid chromatography-tandem mass spectrometry assay, which was able to illustrate the sharp changes in midazolam PK by ketoconazole and pregnenolone 16-carbonitrile as well as phenacetin PK by -naphthoflavone and 3-methylcholanthrene. Surprisingly, 3-methylcholanthrene also decreased systemic exposure to midazolam, whereas both pregnenolone 16-carbonitrile and 3-methylcholanthrene largely reduced the exposure to dextromethorphan, diclofenac, and chlorzoxazone. Finally, the biologic miR-34a agent had no significant effects on the PK of cocktail drugs but caused a marginal (45%-48%) increase in systemic exposure to midazolam, phenacetin, and dextromethorphan in mice. In vitro validation of these data suggested that miR-34a slightly attenuated intrinsic clearance of dextromethorphan. These findings from single-mouse PK and corresponding mouse liver microsome models suggest that miR-34a might have minor or no effects on the PK of coadministered cytochrome P450-metabolized drugs.

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Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest

Cited by 38 publications

References 50 publications

MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers

MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers

Transcription and Translation Inhibitors in Cancer Treatment

Effects of MicroRNA-34a on the Pharmacokinetics of Cytochrome P450 Probe Drugs in Mice

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