Small molecules targeting microRNA for cancer therapy: Promises and obstacles

Wen, Di; Danquah, Michael; Chaudhary, Amit; Mahato, Ram I.

doi:10.1016/j.jconrel.2015.08.011

Cited by 84 publications

(72 citation statements)

References 154 publications

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“…However, the mechanisms underlying the anticancer activities are yet to be elucidated. Studies are currently focussing on the identification and development of small molecules that inhibit major cell signalling pathways, as an important strategy in anticancer drug research (51)(52)(53). The present study investigated the effects of cucurbitacin B on cell proliferation and the MAPK and JAK2/STAT3 pathways in U-2 OS cells.…”

Section: Discussionmentioning

confidence: 99%

Cucurbitacin B inhibits cell proliferation and induces apoptosis in human osteosarcoma cells via modulation of the JAK2/STAT3 and MAPK pathways

Zhang

Gao

Yang

2017

Experimental and Therapeutic Medicine

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Abstract. Osteosarcoma (OS) is the most commonly diagnosed tumor of the bones in children and young adults. Even with conventional therapies the 5-year survival rate is ~65% in patients with OS. Considering the side effects and aggressiveness of malignant bone tumors, research is focussing on multi-targeted strategies in treatment. Cucurbitacin B, a triterpenoid compound has been demonstrated to induce apoptosis in various cancer cell types. The Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling cascades and mitogen activated protein kinases (MAPK) signalling cascades are critical regulators of tumorigenesis. The present study assessed the influence of cucurbitacin B on the viability and expression of MAPKs and proteins of the JAK2/STAT3 cascades in human OS cells (U-2 OS). Cucurbitacin B (20-100 µM) significantly reduced cell viability (P<0.05) and induced apoptosis, as assessed by MTT and Annexin V/propidium iodide staining, along with inhibiting cell migration. Gelatin zymography revealed supressed activities of matrix metalloproteinase (MMP-)2 and 9. Furthermore, cucurbitacin B effectively upregulated the apoptotic pathway and caused the effective inhibition of MAPK signalling and JAK2/STAT3 cascades. Multifold suppression of vascular endothelial growth factor by cucurbitacin B was also observed, indicating inhibition of angiogenesis. Thus, by downregulating major pathways-MAPK and JAK2/STAT3 and MMPs, cucurbitacin B has potent anti-proliferative and anti-metastatic effects that require further investigation with regards to cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Cucurbitacin B inhibits cell proliferation and induces apoptosis in human osteosarcoma cells via modulation of the JAK2/STAT3 and MAPK pathways

Zhang

Gao

Yang

2017

Experimental and Therapeutic Medicine

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“…Aberrantly expressed miRNAs contribute to many biological processes including tumor initiation and progression, apoptosis, and maintenance of CSCs and EMT phenotype [9-11]. Studies including ours have shown the importance of miRNAs and CSCs in cancer progression and metastasis, making their significance as biomarkers and potential targets for reversing drug resistance [12,13].…”

Section: Introductionmentioning

confidence: 99%

Chemosensitization and inhibition of pancreatic cancer stem cell proliferation by overexpression of microRNA-205

et al. 2017

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Treatment of pancreatic cancer with gemcitabine (GEM) is limited due to its rapid plasma metabolism and development of chemoresistance. MicroRNA (miRNA) regulates cancer stem cell (CSC) maintenance and induces chemoresistance in cancer cells. In this study, we observed differential downregulation of miR-205 (miR-205-5p) in human pancreatic cancer tissues and cells. Compared to GEM-sensitive MIA PaCa-2 cells, miR-205 was highly downregulated in GEM-resistant MIA PaCa-2R cells. Lentivirus-mediated overexpression of miR-205 inhibits MIA PaCa-2R cell proliferation after GEM-treatment. Further investigation confirmed that miR-205 alone significantly reduces the proliferation of CSCs and tumor growth in mouse models. However, miR-205 in combination with GEM was more efficient in reducing the proliferation of CSCs and 3D spheroids. Moreover, miR-205 overexpressing MIA PaCa-2R cells induced orthotopic tumor growth was significantly inhibited after intravenous administration of GEM-conjugated methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate)-graft-gemcitabine-graft-dodecanol (mPEG-b-PCC-g-GEM-g-DC) (mPEG-b-PCC-g-GEM-g-DC) polymeric micelles. Also, a reduction in CSCs, EMT and chemoresistance markers was observed in miR-205 overexpressing MIA PaCa-2R cells. Immunohistochemical analysis of orthotopic tumors showed a decrease in drug resistance protein caveolin-1 and cell proliferation marker Ki-67 in combination treatment. Overall, our findings suggest that miR-205 resensitizes GEM-resistant pancreatic cancer cells to GEM and acts as a tumor suppressor miRNA.

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“…Previous studies have demonstrated that miRNAs are involved in regulating several cellular functions, including cell proliferation, apoptosis, motility and differentiation (5,6). Abnormal expression and function of miRNAs has been confirmed to serve important roles in different types of human cancers, including GC (7,8). Multiple miRNAs are regarded as attractive biomarkers and potential therapeutic targets for GC (9,10).…”

Section: Introductionmentioning

confidence: 99%

miR‑449c inhibits migration and invasion of gastric cancer cells by targeting PFKFB3

2018

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Abstract. microRNAs (miRNAs) are important regulators in the development and progression of human gastric cancer (GC). However, the expression and biological function of miR-449c in GC remains unknown. In the present study, miR-449c was demonstrated to be downregulated in GC tissues and cell lines compared with normal. Decreased miR-449c levels were associated with poor prognosis in GC patients. Overexpression of miR-449c inhibited migration and invasion in SGC-7901 cells, while inhibition of miR-449c enhanced migration and invasion in MGC-803 cells. Furthermore, 6-phosphofructo-2-kinase (PFKFB3) was identified to be a downstream target of miR-449c in GC cells. miR-449c directly regulated the expression of PFKFB3 in GC cells. Overexpression of PFKFB3 abrogated the inhibitory effect of miR-449c on the migration and invasion of GC cells. In conclusion, the present study suggests that miR-449c may be a novel biomarker and potential therapeutic target in GC.

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Small molecules targeting microRNA for cancer therapy: Promises and obstacles

Cited by 84 publications

References 154 publications

Cucurbitacin B inhibits cell proliferation and induces apoptosis in human osteosarcoma cells via modulation of the JAK2/STAT3 and MAPK pathways

Cucurbitacin B inhibits cell proliferation and induces apoptosis in human osteosarcoma cells via modulation of the JAK2/STAT3 and MAPK pathways

Chemosensitization and inhibition of pancreatic cancer stem cell proliferation by overexpression of microRNA-205

miR‑449c inhibits migration and invasion of gastric cancer cells by targeting PFKFB3

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