Melanoma is regarded as the most aggressive type of skin malignancy with a poor prognosis. Melanoma cells show the characteristics of chemoresistance and metastasis. Currently, clinical treatment of malignant melanoma mainly relies on surgery. However, postoperative recurrence and cancer metastasis are commonly seen. Meanwhile, the JAK2/STAT3 pathway contributes to tumorigenesis in various cancers and is a promising target for the discovery and development of antitumor therapeutics. Significantly, JAK2/STAT3 signal pathway’s inhibition has been validated that it can induces apoptosis in melanoma cells. Derivatives of amentoflavone have previously been discovered as Type II inhibitors of JAK2. These compounds inhibited JAK2 activity and down-regulated STAT3-directed expression. In this study, we investigated the antitumor potency of amentoflavone derivatives against melanoma. We found that compound 1 showed potent inhibition of JAK2 autophosphorylation and also suppressed the growth of human melanoma cells A375 with an IC50 value of 2.31 μM. Importantly, compound 1 also showed inhibition of STAT3 target proteins Bcl-2, Bax, c-myc, and cyclin D1, which are associated with the regulation of apoptosis and the cell proliferation. Taken together, these results showed that compound 1 represents a promising antitumor agent for melanoma therapy.

黑色素瘤是一類惡性程度極高，疾病進程較快的皮膚癌。由於黑色素瘤容易發 生轉移同時對放化療治療不敏感，因此臨床治療黑色素瘤一般以手術為主，然 而病人朮後也極容易出現癌症復發或者癌細胞轉移。目前癌症靶向治療越來越 受到人們的青睞，對此的研究也越發深入。有研究顯示 JAK2/STAT3 細胞通路 能夠影響多種癌症的惡化進程，對下一代抗癌藥物的研發有積極的影響。研究 顯示抑制 JAK2/STAT3 通路能夠誘導黑色素瘤細胞凋亡，從而影響癌細胞的增 殖。穗花杉雙黃酮的衍生物作為經過優化的JAK2二型抑制劑，具有明顯的拮抗 JAK2 激酶磷酸化的作用並能顯著影響其下游蛋白 STAT3 的表達。本文探討了上 述化合物在黑色素瘤細胞增殖過程中的抗癌活性。結果顯示，在衆多的衍生物 中，化合物 1 能夠抑制黑色素瘤細胞 A375 生長（IC50 = 2.31 μM），並且對 JAK2 蛋白的活化也有較為明顯的抑制。與此同時，對 JAK2 的下游蛋白 STAT3 靶向基因的表達存在相應的影響。例如能夠調控促凋亡蛋白 Bcl-2 和抗凋亡 Bax 的基因表達，以及對能夠影響調控細胞週期的蛋白 cyclin D1 和與細胞生長緊密 聯繫的蛋白 c-myc 的基因表達。給葯處理後的黑色素瘤細胞 A375 最終表現出促 細胞凋亡和抗癌細胞增殖的特點，因此化合物 1 有希望給黑色素瘤的治療帶來 助力。