研究褪黑激素對小細胞肺癌的抗癌活性

Abstract

肺癌是全球高死亡率的癌症之一，其中大部分的肺癌病患屬於非小細胞肺癌(NSCLC)，即便小細胞肺癌(SCLC)只占肺癌病患的百分之十五，小細胞肺癌的快速生長及早期轉移等特性讓小細胞肺癌的病患的存活率相當低。小細胞肺癌的治療方針及藥物的選擇有限的情況下，十幾年以來小細胞肺癌病患的臨床表現不佳，儘管小細胞肺癌的病患在接受第一線化療藥物的效果顯著，小細胞肺癌的病患往往復發率高且經常引發抗藥性的病徵，讓小細胞肺癌的治療相當棘手，且非常迫切需要開發新的治療策略。近年有研究指出melatonin在不同癌症裡表現出褪黑激素抗腫瘤(oncostatic effects)的活性，Melatonin主要是由松果體(pineal gland)及其他器官所分泌的吲哚胺基酸(indoleamine)，主要的生理活性為調節日夜時差及季節轉換，也運用在治療睡眠障礙、時差及頭痛等徵狀。在本篇研究中，我們將針對melatonin在小細胞肺癌中的抗癌活性作探討。實驗結果顯示出melatonin能有效抑制小細胞肺癌的生長且有效地造成細胞死亡，Melatonin 提高小細胞肺癌內sub-G1的比例並且激發caspase-3的活性，小細胞肺癌在melatonin的作用下造成PARP cleavage的成果顯著增加。除此之外，melatonin造成小細胞肺癌內的Erk磷酸化表現量增加，因此，我們使用MEK inhibitor CI-1040 針對melatonin的抗癌機制做更進一步的探討，並發現CI-1040能有效增強melatonin在小細胞肺癌內的毒殺效果。本篇研究最後結論出melatonin具有發展為治療小細胞肺癌藥物的潛力。

Lung cancer is one of the most deadly cancer type worldwide. The majority of lung cancer is non-small cell lung cancer, and the other type is small cell lung cancer (SCLC). Even though SCLC only accounts for 15 percent of lung cancer cases, it still remains high mortality rate because of its rapid growth and aggressive metastasis ability. Limited treatment options make SCLC clinical outcomes with less improvement for decades. Despite that SCLC patients respond to first-line platinum-etoposide (EP) therapy at beginning, they relapse soon after received treatment. Recent studies show oncostatic effects of melatonin, a natural indoleamine which is primarily produced by pineal gland and other organs then released to the blood, in various kinds of tumors. Melatonin has been known for circadian rhythm regulation and been used to treat sleeping disorder, jet-lag and headaches. In this study, we investigated the anticancer activity of melatonin in SCLC cell lines H146 and H209. Results elucidated that melatonin efficiently inhibited cell growth and shown cytotoxicity to the SCLC cell lines. Moreover, melatonin elevated the sub-G1 populations and caspase-3 activities in 24-hour treatment. In addition, melatonin also up-regulated extracellular signal-regulated kinase (Erk) phosphorylation and we used MEK inhibitor CI-1040 in order to investigate the mechanism behind anticancer properties of melatonin. Taken together, we confirmed that melatonin alone has anticancer activity in SCLC. Furthermore, MEK inhibitor CI-1040 promoted melatonin-mediated cell growth inhibition abilities. In summary, we suggest that melatonin might be the novel therapeutic choice for SCLC patients.