近幾年抗癌機轉的研究已漸漸轉往開發特定標靶小分子，藉由鎖定致癌基因作為標靶分子進行攻擊並減少對正常細胞的傷害。此外，學者們也期望由天然物中找到天然致癌抑制劑，來針對疾病治療和降低治療所產生的副作用。山竹有「果后」之稱，其主要活性成分山竹山酮素類化合物(xanthones)近幾年被研究做為致癌因子抑制劑，其在晶體結構鑑定上會與MutT homologue (MTH1)活性位結合，進而抑制MTH1之活性，促使癌細胞死亡。本研究初期研究發現山竹萃取物和山酮素類化合物對人類皮膚細胞之毒殺作用具選擇性，推測其可做為MTH1之抑制劑，可調控正常細胞對抗氧化壓力，抑制皮膚癌細胞之修護，促使癌細胞死亡。目前關於山竹和皮膚相關的文獻，以及MTH1對皮膚及皮膚癌細胞作用的文獻鮮少。本研究擬探討山竹萃取物及山酮素類化合物於皮膚保護及修復、皮膚癌預防及其結合化療藥物之輔助作用機制，進?三大項工作：1.探討山竹萃取物和山酮素類化合物於DNA修復機制、抗氧化性壓力及抗發炎機制在人類皮膚細胞老化及癌化之發生與預防上之角色。2.探討山竹萃取物和山酮素類化合物作為MTH1抑制劑在調控皮膚細胞修復，和促使皮膚癌細胞凋亡之機制。3.探討山竹萃取物和山酮素類化合物透過抑制MTH1表現，增強癌細胞對於化療藥物的敏感性，促使癌細胞死亡。探討山酮素類化合物是否可抑制無毛鼠因紫外線誘導而造成之皮膚損傷及發炎反應；評估山酮素類化合物於預防皮膚癌發生和輔助皮膚癌臨床用藥，降低化療藥物引發之副作用，促進傷口癒合以降低感染風險之能力。期望山竹及山酮素類化合物能更廣泛的應用於皮膚修護及化學預防及治療。 The researches of anti-cancer mechanisms are developed targets with small molecules in recent years gradually. The small units attack malignant cells but not for healthy cells by aiming at oncogene. Additionally, scientists expect that find tumors inhibitors from nature for therapy and side effects decrease. Xanthones, from the Garcinia mangostana (GM) (the queen of fruit), are reported as the tumor inhibitors. They killed the cancer cells by binding to MTH1 (MutT homologue 1) active site, which through X-ray crystallographic screening. In our previous study, we found that the cytotoxic of human skin cells of GM extracts and xanthones are selective. It may act as MTH1 inhibitors, which regulated anti-oxidation stress on healthy cells and inhibited cell repair on the cancer cells. However, there are few studies of GM and MTH1 on skin and skin cancer effects. In this project, we investigate the mechanisms of GM extract and xanthones on skin protection and repair, skin cancer prevention, and adjuvant chemotherapy effects. This project focuses on three aims: 1) the role of GM extracts and xanthones on DNA repair, anti-oxidation, anti-inflammation in human skin cell aging and carcinogenesis mechanisms; 2) the mechanism of GM extracts and xanthones as MTH1 inhibitor on skin cell repair and skin cancer apoptosis; 3) the effects of GM or xanthones as adjuvant traditional Chinese medicine (TCM) combine with the chemotherapeutic drug on enhancing sensitive to cancer cells by inhibiting MTH1 expression. In this section, we assess the inhibition effects on skin injury and inflammation in ultraviolet radiation-caused skin damages models in hairless mice. We also investigate the capacities of wound healing promotion, cell carcinogenesis prevention, side effect and infection reduction from chemotherapy. We expected that GM extracts and xanthones would apply to skin repair, chemoprevention, and therapy widely.
