Antitumor activity of
            the MEK
            inhibitor trametinib on intestinal polyp formation in
            Apc
            Δ716
            mice involves stromal
            COX
            ‐2

The antitumor activities of ethyl acetate extracts fromSelaginella doederleiniiHieron (SD extracts)in vitroandin vivoand its possible mechanism were investigated. HPLC method was developed for chemical analysis. SD extracts were submitted to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay on different cells, flow cytometry, and RT-PCR analysis using HepG2 cell and antitumor activityin vivousing H-22 xenograft tumor mice. Six biflavonoids from SD extracts were submitted to molecular docking assay. The results showed that SD extracts had considerable antitumor activityin vitroandin vivowithout obvious toxicity on normal cells and could induce cell apoptosis. The mechanisms of tumorigenesis and cell apoptosis induced by SD extracts may be associated with decreasing the ratio of bcl-2 and bax mRNA level, activating caspase-3, suppressing survivin, and decreasing the gene expression of COX-2, 5-LOX, FLAP, and 12-LOX mRNA. The main active component in SD extracts is biflavonoids and some exhibited strong interactions with COX-2, 5-LOX, 12-LOX, and 15-LOX. These results offering evidence of possible mechanisms of SD extracts suppress cell proliferation and promote apoptosis and provide the molecular theoretical basis of clinical application ofS. doederleiniifor cancer therapy.

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Molecular Targeting of HuR Oncoprotein Suppresses MITF and Induces Apoptosis in Melanoma Cells

Cancers ◽

10.3390/cancers13020166 ◽

2021 ◽

Vol 13 (2) ◽

pp. 166

Author(s):

Rebaz Ahmed ◽

Ranganayaki Muralidharan ◽

Akhil Srivastava ◽

Sarah E. Johnston ◽

Yan D. Zhao ◽

...

Keyword(s):

Cell Cycle ◽

Drug Resistance ◽

Targeted Therapy ◽

Antitumor Activity ◽

Mek Inhibitor ◽

Melanoma Cells ◽

Migration And Invasion ◽

Mutational Status ◽

The Impact

Background: Treatment of metastatic melanoma possesses challenges due to drug resistance and metastases. Recent advances in targeted therapy and immunotherapy have shown clinical benefits in melanoma patients with increased survival. However, a subset of patients who initially respond to targeted therapy relapse and succumb to the disease. Therefore, efforts to identify new therapeutic targets are underway. Due to its role in stabilizing several oncoproteins’ mRNA, the human antigen R (HuR) has been shown as a promising molecular target for cancer therapy. However, little is known about its potential role in melanoma treatment. Methods: In this study, we tested the impact of siRNA-mediated gene silencing of HuR in human melanoma (MeWo, A375) and normal melanocyte cells in vitro. Cells were treated with HuR siRNA encapsulated in a lipid nanoparticle (NP) either alone or in combination with MEK inhibitor (U0126) and subjected to cell viability, cell-cycle, apoptosis, Western blotting, and cell migration and invasion assays. Cells that were untreated or treated with control siRNA-NP (C-NP) were included as controls. Results: HuR-NP treatment significantly reduced the expression of HuR and HuR-regulated oncoproteins, induced G1 cell cycle arrest, activated apoptosis signaling cascade, and mitigated melanoma cells’ aggressiveness while sparing normal melanocytes. Furthermore, we demonstrated that HuR-NP treatment significantly reduced the expression of the microphthalmia-associated transcription factor (MITF) in both MeWo and MITF-overexpressing MeWo cells (p < 0.05). Finally, combining HuR-NP with U0126 resulted in synergistic antitumor activity against MeWo cells (p < 0.01). Conclusion: HuR-NP exhibited antitumor activity in melanoma cells independent of their oncogenic B-RAF mutational status. Additionally, combinatorial therapy incorporating MEK inhibitor holds promise in overriding MITF-mediated drug resistance in melanoma.

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