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Oxyfadichalcone C inhibits melanoma A375 cell proliferation and metastasis via suppressing PI3K/Akt and MAPK/ERK
Xiaolin Peng1, Zhengming Wang2, Yang Liu3
1Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, PR China; Department of Otorhinolaryngology Head and Neck Surgery, Tianjin First Central Hospital, Tianjin 300192, China.
Aims:
Melanoma remains to be one of the most incurable cancers. Discovery of novel antitumor agent for melanoma therapy is expected. We recently isolated Oxyfadichalcone C from Oxytropis falcate and investigated the anti-proliferative and anti-metastatic activity on human melanoma A375 cells in vitro.
Main Methods:
Cell viability was determined using MTT assay and soft agar cloning formation assay. The effect of Oxyfadichalcone C on cell cycle distribution and apoptosis were analyzed by flow cytometry. Cell metastasis was determined by wound healing assay, Transwell assay and Gelatin zymography assay. The effect of Oxyfadichalcone C on signal proteins of PI3K/Akt and MAPK/ERK pathways was examined by western blot analysis. Synergism assay was employed to determine whether combination of Oxyfadichalcone C with Vemurafenib would enhance the anti-proliferative effect.
Key Findings:
Oxyfadichalcone C potently inhibited proliferation, induced G1 phase arrest and weak apoptosis in A375 cells. Anti-migration and anti-invasion activities were also indicated. Such effects were associated with upregulation of p27, reduction of cyclin D1, p-pRb, p-Integrin β1, as well as the proteolytic activity of metalloproteinase (MMP)-2/9. Meanwhile, key molecules of PI3K/Akt and MAPK/ERK pathways were downregulated, which might be involved in the inhibition against proliferation and metastasis of A375 cells by Oxyfadichalcone C. In addition, combination of Oxyfadichalcone C with Vemurafenib at a ratio of IC50 Oxyfadichalcone C: 5 × IC50 Vemurafenib exhibited synergistic anti-proliferative effect on A375 cells.
Significance:
Our findings suggest that Oxyfadichalcone C has the potential to be developed as a promising drug candidate for the treatment of melanoma.
Insights
Oxyfadichalcone C, a novel compound from Oxytropis falcate, effectively inhibits melanoma cell proliferation and metastasis by impacting key cell signaling pathways. Combination therapy with Vemurafenib shows synergistic anti-proliferative effects, suggesting its potential as a melanoma drug candidate.
Area of Science:
- Natural Product Chemistry
- Cancer Biology
- Pharmacology
Background:
- Melanoma is a highly aggressive and often incurable cancer.
- There is a critical need for novel therapeutic agents to combat melanoma.
- Oxyfadichalcone C is a newly isolated compound from Oxytropis falcate.
Purpose of the Study:
- To investigate the anti-proliferative and anti-metastatic potential of Oxyfadichalcone C.
- To explore the underlying molecular mechanisms of Oxyfadichalcone C's action.
- To evaluate the synergistic effect of Oxyfadichalcone C in combination with Vemurafenib.
Main Methods:
- Cell viability assessed via MTT and soft agar assays.
- Cell cycle and apoptosis analyzed by flow cytometry.
- Metastasis evaluated using wound healing, Transwell, and zymography assays.
- Western blotting used to examine PI3K/Akt and MAPK/ERK signaling pathways.
- Synergism assay performed with Vemurafenib.
Main Results:
- Oxyfadichalcone C inhibited proliferation and induced G1 arrest in A375 melanoma cells.
- The compound demonstrated anti-migration and anti-invasion properties.
- Effects were linked to altered expression of cell cycle regulators (p27, cyclin D1, p-pRb) and MMP-2/9 activity.
- Downregulation of PI3K/Akt and MAPK/ERK pathways was observed.
- Combination with Vemurafenib showed synergistic anti-proliferative activity.
Conclusions:
- Oxyfadichalcone C exhibits significant anti-melanoma activity in vitro.
- The compound modulates key signaling pathways involved in proliferation and metastasis.
- Oxyfadichalcone C shows promise as a potential therapeutic agent for melanoma treatment.
- Combination therapy may enhance treatment efficacy.
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