謝逸憲Yi-Hsien Hsieh葉思妏Sih-Wen Yeh醫學研究所2026-10-299999-12-312022https://handle.ncl.edu.tw/11296/5dq879https://scholars.csmu.edu.tw/handle/123456789/36638子宮內膜癌是女性常見的惡性腫瘤之一，在近十年間，子宮內膜癌的發生率在已開發國家中顯著的增加，且隨著生活方式西化、肥胖人口增加及生育率降低，造成子宮內膜癌罹患風險顯著增加。更重要的是，罹患子宮內膜癌的年齡逐漸年輕化，並造成全球每年有超過4萬名的婦女因此而喪命。然而，目前子宮內膜癌的治療成效有限，因此發展治療子宮內膜癌之新方法及探討新興藥物治療的分子機制尤為重要。印苦楝內酯是從印度苦楝樹葉子中所萃取出來的一種檸檬苦素，以具有抗癌、抗菌、抗發炎等功效聞名。先前的文獻指出，印苦楝內酯在不同的癌症，如:前列腺癌、大腸癌、腎癌等癌症中具有抑癌效果。然而，印苦楝內酯對於子宮內膜癌之抗癌效果及其分子機制目前仍不清楚。因此，本研究欲探討印苦楝內酯對於子宮內膜癌是否具有抗癌功效，及其相關分子機制。實驗結果顯示，印苦楝內酯會誘導Sub G1 phase細胞增加，並抑制生長；造成細胞粒線體膜電位減少，並增加cleaved caspase-3、cleaved PARP、BNIP3和LC3-II蛋白表現量，最終引起細胞凋亡及粒線體自噬作用；造成細胞中脂質ROS堆積和GPX4蛋白表現量減少，引發鐵依賴性死亡。另外，實驗亦發現印苦楝內酯會造成細胞中粒線體ROS堆積，然而，在使用ROS抑制劑NAC後，可有效地抑制印苦楝內酯所誘導的細胞凋亡、粒線體自噬以及鐵依賴性細胞死亡。最後，透過異種移植 (Xenograft model) 之動物實驗及子宮內膜癌患者初代細胞之細胞實驗進行驗證，結果顯示，印苦楝內酯不論是在體外或是體內，皆可有效抑制子宮內膜癌的進展。本研究結果證實，印苦楝內酯可透過誘導子宮內膜癌細胞中粒線體ROS生成，引起細胞凋亡、粒線體自噬以及鐵依賴性死亡，進而抑制子宮內膜癌之進展。期待未來印苦楝內酯成為子宮內膜癌之新興治療藥物，為癌症治療帶來新希望。Endometrial cancer (EC) is one of the most common gynecological malignancies. In the past decade, the incidence of endometrial cancer has increased significantly in developed countries, with the westernization of lifestyle, the increase in the obese population, and fertility decline. The age of onset of endometrial cancer tends to be younger and kills more than 40,000 women worldwide each year. However, the current therapeutic effects of endometrial cancer are limited, so it is essential to develop new methods for the treatment of endometrial cancer and to explore the molecular mechanisms. Nimbolide is a limonoid extracted from the neem tree leaves, known for its anti-cancer, anti-bacterial, and anti-inflammatory properties. Previous literature pointed out that nimbolide has a tumor suppressor effect in different cancers, such as prostate, colorectal, kidney, and other cancers. However, the anti-cancer effect of nimbolide on endometrial cancer and its molecular mechanism is still unclear. Therefore, this study aimed to investigate whether nimbolide has anti-cancer effects on endometrial cancer and its related molecular mechanisms. The experimental results show that nimbolide decreased cell growth and increased the Sub G1 phase; mitochondrial membrane potential depolarization, and increased the expression of cleaved caspase-3, cleaved PARP, BNIP3, and LC3-II proteins, resulting in apoptosis and mitophagy; lipid ROS accumulation and decreased GPX4 protein expression in cells, triggering ferroptosis. In addition, it was also found that nimbolide can induce mitochondrial ROS accumulation in cells, and treatment of NAC, a ROS inhibitor, can effectively inhibit apoptosis, mitophagy, and ferroptosis induced by nimbolide. Results from in vivo animal model and primary endometrial cancer cells were similar to the results from in vitro cell experiments. In conclusion, our results showed that nimbolide could effectively inhibit the progression of endometrial cancer, it may serve as a potential treatment for endometrial cancer in the future.子宮內膜癌印苦楝內酯細胞凋亡粒線體自噬鐵依賴性死亡Endometrial cancerNimbolideApoptosisMitophagyFerroptosisthesis