Topical 2′-Hydroxyflavanone for Cutaneous Melanoma
| Autor: | Aditya Rajan, Sharda P. Singh, William C. Green, Sharad S. Singhal, Michelle Tarbox, Henry Palangdao Igid, Philip Palade, Somedeb Ball, Vijay S. Tonk, Chhanda Bose, Jihyun Lee, Sanjay Awasthi, Ashly Hindle |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research pro-apoptotic signaling ralbp1 rlip76 lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine Epidermal growth factor medicine melanoma Cytotoxicity topical application neoplasms Chemistry Sunitinib Melanoma medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 3. Good health 030104 developmental biology Oncology Mechanism of action Cell culture Apoptosis 030220 oncology & carcinogenesis Cutaneous melanoma Cancer research medicine.symptom 2′-hydroxyflavanone medicine.drug |
| Zdroj: | Cancers, Vol 11, Iss 10, p 1556 (2019) Cancers Volume 11 Issue 10 |
| ISSN: | 2072-6694 |
| Popis: | 2&prime hydroxyflavanone (2HF) is a dietary flavonoid with anticancer activity towardsmultiple cancers. Here, we report that topically applied 2HF inhibits the growth of intradermalimplants of melanoma in immunocompetent mice. 2HF induced apoptosis and inhibited the growthof the human SK-MEL-24 as well as murine B16-F0 and B16-F10 melanoma cell lines in vitro.Apoptosis was associated with depletion of caspase-3, caspase-9, and PARP1 in B16-F0 and SKMEL-24 cells. Caspase-9 and MEKK-15 were undetected even in untreated B16-F10 cells. Signalingproteins TNF&alpha and phospho-PDGFR-&beta were depleted in all three cell lines MEKK-15 was depletedby 2HF in SK-MEL-24 cells. 2HF enhanced sunitinib (an MEK and PDGFR-&beta inhibitor) and AZD2461 (a PARP1 inhibitor) cytotoxicity. 2HF also depleted the Ral-regulated, stress-responsive,antiapoptotic endocytic protein RLIP76 (RALBP1), the inhibition of which has previously beenshown to inhibit B16-F0 melanoma growth in vivo. Functional inhibition of RLIP76 was evidentfrom inhibition of epidermal growth factor (EGF) endocytosis by 2HF. We found that topicallyapplied 2HF&ndash Pluronic Lecithin Organogel (PLO) gel inhibited B16-F0 and B16-F10 tumorsimplanted in mice and caused no overt toxicity despite significant systemic absorption. 2HFtreatment reduced phospho-AKT, vimentin, fibronectin, CDK4, cyclinB1, and BCL2, whereas itincreased BIM and phospho-AMPK in excised tumors. Several cancer signals are controlled byendocytosis, a process strongly inhibited by RLIP76 depletion. We conclude that 2HF&ndash PLO gel maybe useful for topical therapy of cutaneous metastases of melanoma and could enhance theantineoplastic effects of sunitinib and PARP1 inhibitors. The mechanism of action of 2HF inmelanoma overlaps with RLI76 inhibitors. |
| Databáze: | OpenAIRE |
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