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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA
Published on: December 19, 2019
Orobol, 3'-hydroxy-genistein, suppresses the development and regrowth of cutaneous SCC
Eunmiri Roh1, Jong-Eun Kim2, Tianshun Zhang3
1Department of Cosmetic Science, Kwangju Women's University, Gwangju 62396, Republic of Korea.
Abstract:
Chronic solar ultraviolet exposure is a major risk factor for cutaneous squamous cell carcinoma (cSCC), which is the second most common type of skin cancer. Our previous data showed that total protein and phosphorylation levels of T-LAK cell-originated protein kinase (TOPK) were enhanced in solar-simulated light (SSL)-induced skin carcinogenesis and overexpressed in actinic keratosis (AK) and cSCC human skin tissues compared to those in matched normal skin. Thus, targeting TOPK activity could be a helpful approach for treating cSCC. Our data showed that orobol directly binds to TOPK in an ATP-independent manner and inhibits TOPK kinase activity. Furthermore, orobol inhibited anchorage-independent colony formation by SCC12 cells in a dose-dependent manner. After discontinuing the treatment, patients commonly return to tumor-bearing conditions; therefore, therapy or intermittent dosing of drugs must be continued indefinitely. Thus, to examine the efficacy of orobol against the development and regrowth of cSCC, we established mouse models including prevention, and therapeutic models on the chronic SSL-irradiated SKH-1 hairless mice. Early treatment with orobol attenuates chronic SSL-induced cSCC development. Furthermore, orobol showed therapeutic efficacy after the formation of chronic SSL irradiation-induced tumor. In the mouse model with intermittent dosing of orobol, our data showed that re-application of orobol is effective for reducing tumor regrowth after discontinuation of treatment. Moreover, oncogenic protein levels were significantly attenuated by orobol treatment in the SSL-stimulated human skin. Thus, we suggest that orobol, as a promising TOPK inhibitor, could have an effective clinical approach to prevent and treat the development and regrowth of cSCC.
Insights
Orol, a T-LAK cell-originated protein kinase (TOPK) inhibitor, effectively prevents and treats skin cancer (cSCC) development and regrowth in mouse models. Intermittent dosing shows promise for long-term management of cSCC.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Chronic solar ultraviolet (UV) exposure is a primary risk factor for cutaneous squamous cell carcinoma (cSCC).
- T-LAK cell-originated protein kinase (TOPK) is overexpressed in actinic keratosis (AK) and cSCC, suggesting its role in skin carcinogenesis.
- Targeting TOPK activity presents a potential therapeutic strategy for cSCC.
Purpose of the Study:
- To investigate the efficacy of orobol, a novel TOPK inhibitor, in preventing and treating cSCC.
- To evaluate orobol's potential for managing cSCC regrowth, particularly with intermittent dosing strategies.
- To assess the impact of orobol on oncogenic protein levels in UV-exposed human skin.
Main Methods:
- In vitro studies demonstrating orobol's direct binding to TOPK and inhibition of its kinase activity.
- Assessment of orobol's effect on anchorage-independent colony formation in SCC12 cells.
- Establishment of mouse models (prevention, therapeutic, and intermittent dosing) using chronic solar-simulated light (SSL)-irradiated SKH-1 hairless mice.
Main Results:
- Orol directly inhibits TOPK kinase activity in an ATP-independent manner and reduces SCC12 cell colony formation.
- Early orobol treatment attenuated SSL-induced cSCC development, and therapeutic administration showed efficacy post-tumor formation.
- Intermittent orobol dosing effectively reduced tumor regrowth after treatment discontinuation, and oncogenic protein levels were decreased in SSL-stimulated human skin.
Conclusions:
- Orol demonstrates significant potential as a therapeutic agent for preventing and treating cSCC.
- The intermittent dosing strategy suggests orobol's utility for long-term cSCC management and preventing recurrence.
- Orol represents a promising clinical approach targeting TOPK for cSCC prevention and treatment.
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