探討SC-43在犬乳腺瘤上的抗癌效果

Abstract

犬乳腺瘤在母犬是十分常見的癌症疾病,其中約有五成病例被診斷為惡性腫 瘤。目前的治療方針以手術切除為大宗,然而仍約有七成的惡性腫瘤在術後會有 復發的併發症,其他治療方式像是化學療法等輔助療法目前在犬乳腺瘤尚未建立 十分有效的治療結果,因此目前需要針對犬乳腺瘤來開發新的輔助療法如小分子 藥物以增進治療效果。STAT3 為一致癌蛋白,調控多種細胞反應如細胞增生、存 活以及組織血管新生等,在人及狗的多種腫瘤包含乳房腫瘤都顯示 STAT3 有過度 表現的情況。本研究探討現行用來治療肝癌的小分子藥物 Sorafenib 其衍生物 SC-43 於犬乳腺瘤的抗癌效果及機制。根據先前的文獻,SC-43 在人類乳癌上對於磷酸化 STAT3(p-STAT3)展現出比原型藥物 Sorafenib 更好的活性抑制,進而誘導腫瘤 細胞產生細胞凋亡。本研究指出,SC-43 在三株犬乳腺瘤細胞上都展現出藉由促進 細胞凋亡,以抑制腫瘤細胞生長的能力。此外,藉由轉殖 STAT3 基因到犬乳腺瘤 細胞上使其過度表現 STAT3 來逆轉藥物促細胞凋亡的結果,顯示 SC-43 乃經由負 調控 p-STAT3 以及下游相關蛋白如 Mcl-1 和 cyclin D1 來達到抑制腫瘤生長及細 胞凋亡的藥效。進一步的研究發現,給予 SHP-1 抑制劑後,SC-43 促細胞凋亡的 藥效亦被逆轉,可顯示出 SC-43 是藉由調升 SHP-1 的活性達到使 p-STAT3 去磷酸 化與負調控下游細胞傳訊路徑的作用。總結來說,SC-43 藉由調控 SHP-1 的活性 來抑制 STAT3 的活化,誘導細胞凋亡,進而在犬乳腺瘤細胞上達到抗癌作用的效 果。

Canine mammary gland tumor (cMGT) is the most common malignancy in female dog. Approximately 50% of these neoplasms are diagnosed as malignant, and distant metastases are common causes of death in these patients. In Taiwan, the primary choice of therapy is surgical treatment, however, over 70% malignant cMGT dogs following lumpectomy have developed secondary mammary tumors and no single adjuvant chemotherapy protocol has been reported to be effective in the dog. Therefore, development of novel therapeutic agents against cMGT is necessary to improve the efficacy of existing therapy. Signal transducer and activator of transcription 3 (STAT3), which is considered as oncoprotein and play crucial role in cell proliferatioin, survival and angiogenesis, is constitutively activated in a verity of human and canine cancers including mammary neoplasms. SC-43, a novel sorafenib derivative targeted STAT3, is found more potency in phospho-STAT3 (p-STAT3) inhibition and apoptosis induction in human breast cancer compared to sorafenib. In this study, SC-43 demonstrated more apoptosis-inducing activity on cMGT cell lines in comparison with sorafenib and it presented in a does- and time-dependent manner. Our results validated by STAT3 transient overexpression suggest that down-regulation of p-STAT3 and its downdtream proteins Mcl-1 (myeloid cell leukemia 1) and cyclin D1 were attribute to antitumor effect of SC-43. Additionally, inhibitor of SHP-1 (SH2-domain containing tyrosine III phosphatase 1) recued the apoptotic effect in cMGT cells via reversing down-regulation of p-STAT3. In conclusion, these finding may indicate that SC-43 induced apoptosis to suppress the growth of cMGT cells thought regulating the SHP-1-depenent STAT3 inhibition.