簡易檢索 / 詳目顯示

研究生: 陳晴盈
Chen, Ching-Ying
論文名稱: 透過生物資訊學探討Ferroptosis在人類大腸直腸癌細胞中植化素Withaferin A合併鉑金類抗癌藥物的角色
The role of Ferroptosis in the combination treatment of Withaferin A and platinum anticancer agent in human colorectal cancer cells via bioinformatics analysis
指導教授: 蘇純立
Su, Chun-Li
口試委員: 蘇純立
Su, Chun-Li
黃奇英
Huang, Chi-Ying
劉校生
Liu, Hsiao-Sheng
蕭寧馨
Shaw, Ning-Shin
口試日期: 2024/07/04
學位類別: 碩士
Master
系所名稱: 營養科學碩士學位學程
Graduate Program of Nutrition Science
論文出版年: 2024
畢業學年度: 112
語文別: 中文
論文頁數: 115
中文關鍵詞: Ferroptosis大腸直腸癌CisplatinWithaferin AFerritinophagy
英文關鍵詞: Ferroptosis, Colorectal cancer, Cisplatin, Withaferin A, Ferritinophagy
研究方法: 實驗設計法
DOI URL: http://doi.org/10.6345/NTNU202401461
論文種類: 學術論文
相關次數: 點閱:111下載:1
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  • 在大腸直腸癌(Colorectal cancer,CRC)中,鉑金類藥物Cisplatin(Cis)的藥物不敏感與副作用的特性已成為十分嚴重問題。鐵依賴型細胞死亡(Ferroptosis)是透過增加細胞內游離鐵堆積並促進脂質過氧化物生成所導致的新型態細胞死亡機制。透過生物資訊學分析結果發現Cis藥物阻抗的CRC患者體內較藥物敏感的患者具有鐵代謝失調的問題。CRC組織較其他癌症組織有堆積較多二價鐵離子的潛力,並且CRC組織相較於正常組織有累積較多游離鐵與促進脂質過氧化物形成的特性,因此透過二價游離鐵促進細胞活性氧物質生成與降低抗氧化能力來誘導Ferroptosis將有機會改善CRC較低的無復發存活率。此外,相較於HCT116,Ferroptosis促進劑RSL3在HT-29中能引起更高的生長抑制作用,並且可以被Ferroptosis抑制劑Ferrostatin-1和Deferoxamine逆轉細胞生長抑制。同時HT-29中有較低的出鐵蛋白表現,代表細胞中可透過增加細胞內游離鐵來促進Ferroptosis。生物資訊學分析結果發現南非醉茄的酯類成分Withaferin A(WA)具有誘導Ferroptosis的潛力,並且在CRC中WA較Cis有較佳的藥物敏感性。合併Cis與WA能夠促進HT-29進行Ferroptosis相關生長抑制、脂質過氧化物累積、游離鐵累積與降低GPX4蛋白表現。此外,合併Cis與WA能增加shGFP HT-29的細胞生長抑制與促進ferritin與LC3B蛋白共位的情形,而這些結果在加入合併藥物的shATG5 HT-29會被抑制,代表Cis與WA可以增加細胞進行ferrtinophagy。綜合以上結果,本研究利用生物資訊學與實驗數據證實在CRC中植化素WA合併Cis能產生協同作用並促進Ferroptosis。

    Drug resistance and side effect in Cisplatin (Cis) had become a serious problem in colorectal cancer (CRC). Ferroptosis is an iron-dependent regulated cell death caused by toxic lipid peroxidation. Through bioinformatics analysis, we discovered that Cis-resistant CRC patients exhibit iron metabolism disorders compared to the Cis-sensitive patients. Besides, CRC tissues, in contrast to other cancer tissues and normal tissues near by the CRC, tended to accumulate Fe2+ and promote lipid peroxidation. Therefore, inducing ferroptosis by increasing intracellular Fe2+ and reducing antioxidant capacity may improve the low relapse-free survival rate in CRC. Compared to HCT116, ferroptosis inducer RSL3 induced a higher growth inhibition in HT-29, and the growth inhibition was reduced by ferroptosis inhibitor Ferrostatin-1 and Deferoxamine. This observation is associated with a lower ferroportin in HT-29, indicating that increasing labile iron pool can promote Ferroptosis in HT-29. By analyzing the transcriptomics data, natural compound Withaferin A (WA) derived from Withania somnifera has the potential to induce Ferroptosis, and WA exhibits better drug sensitivity in CRC compared to Cis. Combination of Cis and WA-induced Ferroptosis in HT-29 was characterized by increasing growth inhibition and repressing GPX4 protein expression, also increasing lipid peroxides and cellular Fe2+ accumulation. Furthermore, the combination of Cis and WA increased growth inhibition and promoted the colocalization of ferritin and LC3B in shGFP HT-29 cells, while these effects were suppressed in Cis and WA treated shATG 5 HT-29 cells, indicating that Cis and WA enhanced ferritinophagy in HT-29 cells. Collectively, our unique integrated screening results and experimental data support the combination of natural compound WA and Cisplatin in producing synergistic effects and inducing ferroptosis in CRC.

    1. 緒論 1 1.1. 大腸直腸癌 1 1.1.1. 流行病學 1 1.1.2. 大腸直腸癌臨床治療困境 2 1.2. 鐵與癌症 2 1.3. Cisplatin 3 1.4. 鐵依賴型細胞死亡(Ferroptosis) 4 1.4.1. 鐵依賴型細胞死亡機轉 5 1.4.1.1. 游離鐵的增加 5 1.4.1.2. 細胞膜上脂質過氧化物的累積 6 1.4.1.3. 抗氧化能力下降 7 1.4.2. Ferroptosis在大腸直腸癌治療上的潛力 7 1.5. Withaferin A(WA)8 2. 研究目的 10 2.1. 確認大腸直腸癌是否適合作為誘導Ferroptosis的癌症類別,並且挑選出合適的大腸直腸癌細胞株 10 2.2. 透過生物資訊學預測具有誘導大腸直腸癌進行Ferroptosis的植化素 11 2.3. 檢測Cisplatin與WA誘導的大腸直腸癌死亡機制是否與Ferroptosis相關並探討可能的機轉 11 3. 材料與方法 13 3.1. 藥品與試劑 13 3.2. 實驗耗材與儀器 16 3.3. 實驗方法 22 3.3.1. 細胞培養、繼代、解凍與冷凍保存 22 3.3.1.1. 細胞培養與繼代 24 3.3.1.2. 細胞解凍 24 3.3.1.3. 細胞冷凍保存 25 3.3.1.4.細胞計數 25 3.3.2. 藥品配置 26 3.3.2.1. (1S, 3R)-RSL3 (RSL3) 26 3.3.2.2. Deferoxamine mesylate salt 26 3.3.2.3. Ferrostatin-1 (Fer-1) 26 3.3.2.4. Withaferin A (WA) 26 3.3.3. 生物資訊學分析 27 3.3.3.1. Xena 27 3.3.3.2. KM-plotter 27 3.3.3.3. Gene set enrichment analysis (GSEA) 27 3.3.3.4. Dependency Map (DepMap) 27 3.3.3.5. CLUE database、ConsensusPathDB (CPDB) 28 3.3.3.6. NCI-60 28 3.3.4. 細胞存活率 28 3.3.5. 西方墨點法 (Western blotting) 29 3.3.5.1. 細胞蛋白製備 (Preparation of whole cell lysate) 29 3.3.5.2. 蛋白質濃度定量 (Quantitation of protein concentration) 30 3.3.5.3. 聚丙烯醯胺膠體電泳 (SDS-polyacrylamide gel electrophoresis) 31 3.3.5.4. 蛋白質樣品配製(Preparation of protein samples) 34 3.3.5.5. 電泳(Electrophoresis) 34 3.3.5.6. 蛋白質轉漬(Transfer) 35 3.3.5.7. 抗體雜交與顯影(Immunoblotting and imaging) 36 3.3.6. 細胞游離鐵分析 (Labile iron pool analysis) 39 3.3.6.1. FerroOrange 39 3.3.6.2. Phen green SK (PGSK) 40 3.3.7. 脂質過氧化物分析(Lipid peroxidation analysis)41 3.3.8. 免疫螢光染色 (Immunofluorescence,IF) 43 3.3.9. 還原態GSH含量分析 45 3.4. 統計分析 (Statistical analysis) 49 4. 實驗結果 50 4.1. 大腸直腸癌是具有潛力誘導Ferroptosis的癌症類別 50 4.2. HT-29對於RSL3有較佳的敏感性 57 4.3. 大腸直腸癌細胞Ferroptosis相關蛋白表現量的差異 60 4.4. 植化素WA適合誘導大腸直腸癌細胞進行Ferroptosis 63 4.5. 在HT-29中Cisplatin與WA能誘導大腸直腸癌細胞鐵依賴型死亡並促進協同作用 67 4.6. Cisplatin與WA誘導大腸直腸癌細胞二價游離鐵累積 72 4.7. Cisplatin與WA誘導大腸直腸癌細胞脂質過氧化物的生成 76 4.8. HT-29加入Cisplatin與WA後在不同時間點影響Ferroptosis相關蛋白的表現量差異 79 4.9Cisplatin與WA誘導大腸直腸癌細胞進行Ferritinophagy 82 5.討論 90 5.1. 鐵代謝平衡對大腸直腸癌發展的影響 90 5.2. 大腸直腸癌抗癌藥物Cisplatin治療困境與解決方法 93 5.3. 合併植化素WA對Cisplatin治療大腸直腸癌的影響 95 6. 結論 99 7. 參考文獻 100 8. 補充圖次 107 7. 附錄圖次 114

    衛生福利部(2023)‧110年國人死因統計結果‧取自https://www.mohw.gov.tw/cp-16-70314-1.html
    AH., K., F., A., R., M., & RC., G. (2020). Synergistic combinations of paclitaxel and withaferin A against human non-small cell lung cancer cells.
    Alnuqaydan AM, R. B., Almutary AG, Chauhan SS. (2020). Synergistic antitumor effect of 5-fluorouracil and withaferin-A induces endoplasmic reticulum stress-mediated autophagy and apoptosis in colorectal cancer cells.
    Brookes, M. J., Hughes, S., Turner, F. E., Reynolds, G., Sharma, N., Ismail, T., Berx, G., McKie, A. T., Hotchin, N., Anderson, G. J., Iqbal, T., & Tselepis, C. (2006). Modulation of iron transport proteins in human colorectal carcinogenesis. Gut, 55(10), 1449-1460. https://doi.org/10.1136/gut.2006.094060
    Bungau, S., Vesa, C. M., Abid, A., Behl, T., Tit, D. M., Purza, A. L., Pasca, B., Todan, L. M., & Endres, L. (2021). Withaferin A-A Promising Phytochemical Compound with Multiple Results in Dermatological Diseases. Molecules, 26(9). https://doi.org/10.3390/molecules26092407
    Chaudhary, N., Choudhary, B. S., Shah, S. G., Khapare, N., Dwivedi, N., Gaikwad, A., Joshi, N., Raichanna, J., Basu, S., Gurjar, M., P, K. S., Saklani, A., Gera, P., Ramadwar, M., Patil, P., Thorat, R., Gota, V., Dhar, S. K., Gupta, S., Das, M., & Dalal, S. N. (2021). Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer. Int J Cancer, 149(7), 1495-1511. https://doi.org/10.1002/ijc.33711
    Chen, P., Li, X., Zhang, R., Liu, S., Xiang, Y., Zhang, M., Chen, X., Pan, T., Yan, L., Feng, J., Duan, T., Wang, D., Chen, B., Jin, T., Wang, W., Chen, L., Huang, X., Zhang, W., Sun, Y., Li, G., Kong, L., Chen, X., Li, Y., Yang, Z., Zhang, Q., Zhuo, L., Sui, X., & Xie, T. (2020). Combinative treatment of beta-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transformation. Theranostics, 10(11), 5107-5119. https://doi.org/10.7150/thno.44705
    Chen, W. C., Wang, C. Y., Hung, Y. H., Weng, T. Y., Yen, M. C., & Lai, M. D. (2016). Systematic Analysis of Gene Expression Alterations and Clinical Outcomes for Long-Chain Acyl-Coenzyme A Synthetase Family in Cancer. PLoS One, 11(5), e0155660. https://doi.org/10.1371/journal.pone.0155660
    Chen, X., Kang, R., Kroemer, G., & Tang, D. (2021). Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol, 18(5), 280-296. https://doi.org/10.1038/s41571-020-00462-0
    Chen, X., Zhu, N., Wu, Y., Zhang, Y., Zhang, Y., Jin, K., Zhou, Z., Chen, G., & Wang, J. (2024). Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells. Phytomedicine, 128, 155317. https://doi.org/10.1016/j.phymed.2023.155317
    Chen, Y., Fan, Z., Yang, Y., & Gu, C. (2019). Iron metabolism and its contribution to cancer (Review). Int J Oncol, 54(4), 1143-1154. https://doi.org/10.3892/ijo.2019.4720
    Chien, T. M., Wu, K. H., Chuang, Y. T., Yeh, Y. C., Wang, H. R., Yeh, B. W., Yen, C. H., Yu, T. J., Wu, W. J., & Chang, H. W. (2021). Withaferin A Triggers Apoptosis and DNA Damage in Bladder Cancer J82 Cells through Oxidative Stress. Antioxidants (Basel), 10(7). https://doi.org/10.3390/antiox10071063
    Chua, A. C., Klopcic, B., Lawrance, I. C., Olynyk, J. K., & Trinder, D. (2010). Iron: an emerging factor in colorectal carcinogenesis. World J Gastroenterol, 16(6), 663-672. https://doi.org/10.3748/wjg.v16.i6.663
    Cohen, S. M., Mukerji, R., Timmermann, B. N., Samadi, A. K., & Cohen, M. S. (2012). A novel combination of withaferin A and sorafenib shows synergistic efficacy against both papillary and anaplastic thyroid cancers. Am J Surg, 204(6), 895-900; discussion 900-891. https://doi.org/10.1016/j.amjsurg.2012.07.027
    Dai, G., Wang, D., Ma, S., Hong, S., Ding, K., Tan, X., & Ju, W. (2022). ACSL4 promotes colorectal cancer and is a potential therapeutic target of emodin. Phytomedicine, 102, 154149. https://doi.org/10.1016/j.phymed.2022.154149
    Devabattula, G., Panda, B., Yadav, R., & Godugu, C. (2024). The Potential Pharmacological Effects of Natural Product Withaferin A in Cancer: Opportunities and Challenges for Clinical Translation. Planta Med, 90(6), 440-453. https://doi.org/10.1055/a-2289-9600
    Doll, S., Proneth, B., Tyurina, Y. Y., Panzilius, E., Kobayashi, S., Ingold, I., Irmler, M., Beckers, J., Aichler, M., Walch, A., Prokisch, H., Trumbach, D., Mao, G., Qu, F., Bayir, H., Fullekrug, J., Scheel, C. H., Wurst, W., Schick, J. A., Kagan, V. E., Angeli, J. P., & Conrad, M. (2017). ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol, 13(1), 91-98. https://doi.org/10.1038/nchembio.2239
    Estevao, D., da Cruz-Ribeiro, M., Cardoso, A. P., Costa, A. M., Oliveira, M. J., Duarte, T. L., & da Cruz, T. B. (2023). Iron metabolism in colorectal cancer: a balancing act. Cell Oncol (Dordr), 46(6), 1545-1558. https://doi.org/10.1007/s13402-023-00828-3
    Florea, A. M., & Busselberg, D. (2011). Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel), 3(1), 1351-1371. https://doi.org/10.3390/cancers3011351
    Galluzzi, L., Senovilla, L., Vitale, I., Michels, J., Martins, I., Kepp, O., Castedo, M., & Kroemer, G. (2012). Molecular mechanisms of cisplatin resistance. Oncogene, 31(15), 1869-1883. https://doi.org/10.1038/onc.2011.384
    Gao, M., Monian, P., Pan, Q., Zhang, W., Xiang, J., & Jiang, X. (2016). Ferroptosis is an autophagic cell death process. Cell Res, 26(9), 1021-1032. https://doi.org/10.1038/cr.2016.95
    Ge, C., Zhang, S., Mu, H., Zheng, S., Tan, Z., Huang, X., Xu, C., Zou, J., Zhu, Y., Feng, D., & Aa, J. (2021). Emerging Mechanisms and Disease Implications of Ferroptosis: Potential Applications of Natural Products. Front Cell Dev Biol, 9, 774957. https://doi.org/10.3389/fcell.2021.774957
    Guo, J., Xu, B., Han, Q., Zhou, H., Xia, Y., Gong, C., Dai, X., Li, Z., & Wu, G. (2018). Ferroptosis: A Novel Anti-tumor Action for Cisplatin. Cancer Res Treat, 50(2), 445-460. https://doi.org/10.4143/crt.2016.572
    Han, S., Yang, X., Zhuang, J., Zhou, Q., Wang, J., Ru, L., Niu, F., & Mao, W. (2024). α-Hederin promotes ferroptosis and reverses cisplatin chemoresistance in non-small cell lung cancer.
    Hassannia, B., Wiernicki, B., Ingold, I., Qu, F., Van Herck, S., Tyurina, Y. Y., Bayir, H., Abhari, B. A., Angeli, J. P. F., Choi, S. M., Meul, E., Heyninck, K., Declerck, K., Chirumamilla, C. S., Lahtela-Kakkonen, M., Van Camp, G., Krysko, D. V., Ekert, P. G., Fulda, S., De Geest, B. G., Conrad, M., Kagan, V. E., Vanden Berghe, W., Vandenabeele, P., & Vanden Berghe, T. (2018). Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Invest, 128(8), 3341-3355. https://doi.org/10.1172/JCI99032
    He, G., He, G., Zhou, R., Pi, Z., Zhu, T., Jiang, L., & Xie, Y. (2016). Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo. Biochem Biophys Res Commun, 469(4), 1075-1082. https://doi.org/10.1016/j.bbrc.2015.12.100
    Horniblow, R. D., Bedford, M., Hollingworth, R., Evans, S., Sutton, E., Lal, N., Beggs, A., Iqbal, T. H., & Tselepis, C. (2017). BRAF mutations are associated with increased iron regulatory protein-2 expression in colorectal tumorigenesis. Cancer Sci, 108(6), 1135-1143. https://doi.org/10.1111/cas.13234
    Hou, W., Xie, Y., Song, X., Sun, X., Lotze, M. T., Zeh, H. J., 3rd, Kang, R., & Tang, D. (2016). Autophagy promotes ferroptosis by degradation of ferritin. Autophagy, 12(8), 1425-1428. https://doi.org/10.1080/15548627.2016.1187366
    Huang, J., Chen, J., & Li, J. (2024). Quercetin promotes ATG5-mediating autophagy-dependent ferroptosis in gastric cancer. J Mol Histol, 55(2), 211-225. https://doi.org/10.1007/s10735-024-10186-5
    Hur, J., Otegbeye, E., Joh, H. K., Nimptsch, K., Ng, K., Ogino, S., Meyerhardt, J. A., Chan, A. T., Willett, W. C., Wu, K., Giovannucci, E., & Cao, Y. (2021). Sugar-sweetened beverage intake in adulthood and adolescence and risk of early-onset colorectal cancer among women. Gut, 70(12), 2330-2336. https://doi.org/10.1136/gutjnl-2020-323450
    Jiang, X., Stockwell, B. R., & Conrad, M. (2021). Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol, 22(4), 266-282. https://doi.org/10.1038/s41580-020-00324-8
    Kakar, S. S., Jala, V. R., & Fong, M. Y. (2012). Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines. Biochem Biophys Res Commun, 423(4), 819-825. https://doi.org/10.1016/j.bbrc.2012.06.047
    Koberle, B., & Schoch, S. (2021). Platinum Complexes in Colorectal Cancer and Other Solid Tumors. Cancers (Basel), 13(9). https://doi.org/10.3390/cancers13092073
    Kyakulaga, A. H., Aqil, F., Munagala, R., & Gupta, R. C. (2018). Withaferin A inhibits Epithelial to Mesenchymal Transition in Non-Small Cell Lung Cancer Cells. Sci Rep, 8(1), 15737. https://doi.org/10.1038/s41598-018-34018-1
    Lin, P. L., Tang, H. H., Wu, S. Y., Shaw, N. S., & Su, C. L. (2020). Saponin Formosanin C-induced Ferritinophagy and Ferroptosis in Human Hepatocellular Carcinoma Cells. Antioxidants (Basel), 9(8). https://doi.org/10.3390/antiox9080682
    Ma, M. Z., Chen, G., Wang, P., Lu, W. H., Zhu, C. F., Song, M., Yang, J., Wen, S., Xu, R. H., Hu, Y., & Huang, P. (2015). Xc- inhibitor sulfasalazine sensitizes colorectal cancer to cisplatin by a GSH-dependent mechanism. Cancer Lett, 368(1), 88-96. https://doi.org/10.1016/j.canlet.2015.07.031
    Manz, D. H., Blanchette, N. L., Paul, B. T., Torti, F. M., & Torti, S. V. (2016). Iron and cancer: recent insights. Ann N Y Acad Sci, 1368(1), 149-161. https://doi.org/10.1111/nyas.13008
    Miotto, G., Rossetto, M., Di Paolo, M. L., Orian, L., Venerando, R., Roveri, A., Vuckovic, A. M., Bosello Travain, V., Zaccarin, M., Zennaro, L., Maiorino, M., Toppo, S., Ursini, F., & Cozza, G. (2020). Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol, 28, 101328. https://doi.org/10.1016/j.redox.2019.101328
    Mármol, I., Sánchez-de-Diego, C., Pradilla Dieste, A., Cerrada, E., & Rodriguez Yoldi, M. (2017). Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer. International Journal of Molecular Sciences, 18(1). https://doi.org/10.3390/ijms18010197
    Osborne, N. J., Gurrin, L. C., Allen, K. J., Constantine, C. C., Delatycki, M. B., McLaren, C. E., Gertig, D. M., Anderson, G. J., Southey, M. C., Olynyk, J. K., Powell, L. W., Hopper, J. L., Giles, G. G., & English, D. R. (2010). HFE C282Y homozygotes are at increased risk of breast and colorectal cancer. Hepatology, 51(4), 1311-1318. https://doi.org/10.1002/hep.23448
    Osman, A. M., Al-Malki, H. S., Al-Harthi, S. E., El-Hanafy, A. A., Elashmaoui, H. M., & Elshal, M. F. (2015). Modulatory role of resveratrol on cytotoxic activity of cisplatin, sensitization and modification of cisplatin resistance in colorectal cancer cells. Mol Med Rep, 12(1), 1368-1374. https://doi.org/10.3892/mmr.2015.3513
    Pino, M. S., & Chung, D. C. (2010). The chromosomal instability pathway in colon cancer. Gastroenterology, 138(6), 2059-2072. https://doi.org/10.1053/j.gastro.2009.12.065
    Rajkumar, P., Mathew, B. S., Das, S., Isaiah, R., John, S., Prabha, R., & Fleming, D. H. (2016). Cisplatin Concentrations in Long and Short Duration Infusion: Implications for the Optimal Time of Radiation Delivery. J Clin Diagn Res, 10(7), XC01-XC04. https://doi.org/10.7860/JCDR/2016/18181.8126
    Sehm, T., Rauh, M., Wiendieck, K., Buchfelder, M., Eyüpoglu, I. Y., & Savaskan, N. E. (2016). Temozolomide toxicity operates in a xCT SLC7a11 dependent manner and is fostered by ferroptosis.pdf.
    Sharma, S., Joshi, A., & Hemalatha, S. (2017). Protective Effect of Withania coagulans Fruit Extract on Cisplatin-induced Nephrotoxicity in Rats. Pharmacognosy Res, 9(4), 354-361. https://doi.org/10.4103/pr.pr_1_17
    Sornjai, W., Nguyen Van Long, F., Pion, N., Pasquer, A., Saurin, J. C., Marcel, V., Diaz, J. J., Mertani, H. C., & Smith, D. R. (2020). Iron and hepcidin mediate human colorectal cancer cell growth. Chem Biol Interact, 319, 109021. https://doi.org/10.1016/j.cbi.2020.109021
    Sui, X., Zhang, R., Liu, S., Duan, T., Zhai, L., Zhang, M., Han, X., Xiang, Y., Huang, X., Lin, H., & Xie, T. (2018). RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer. Front Pharmacol, 9, 1371. https://doi.org/10.3389/fphar.2018.01371
    Tang, D., Chen, X., Kang, R., & Kroemer, G. (2021). Ferroptosis: molecular mechanisms and health implications. Cell Res, 31(2), 107-125. https://doi.org/10.1038/s41422-020-00441-1
    Thanikachalam, K., & Khan, G. (2019). Colorectal Cancer and Nutrition. Nutrients, 11(1). https://doi.org/10.3390/nu11010164
    Torti, S. V., & Torti, F. M. (2013). Iron and cancer: more ore to be mined. Nat Rev Cancer, 13(5), 342-355. https://doi.org/10.1038/nrc3495
    Vyas, A. R., & Singh, S. V. (2014). Molecular targets and mechanisms of cancer prevention and treatment by withaferin a, a naturally occurring steroidal lactone. AAPS J, 16(1), 1-10. https://doi.org/10.1208/s12248-013-9531-1
    Wang, Y., Zhang, Z., Sun, W., Zhang, J., Xu, Q., Zhou, X., & Mao, L. (2022). Ferroptosis in colorectal cancer: Potential mechanisms and effective therapeutic targets. Biomed Pharmacother, 153, 113524. https://doi.org/10.1016/j.biopha.2022.113524
    Wilson, M. J., Harlaar, J. J., Jeekel, J., Schipperus, M., & Zwaginga, J. J. (2018). Iron therapy as treatment of anemia: A potentially detrimental and hazardous strategy in colorectal cancer patients. Med Hypotheses, 110, 110-113. https://doi.org/10.1016/j.mehy.2017.12.011
    Wu, J., Liao, Q., Zhang, L. I., Wu, S., & Liu, Z. (2023). TGF-beta-regulated different iron metabolism processes in the development and cisplatin resistance of ovarian cancer. Oncol Res, 32(2), 373-391. https://doi.org/10.32604/or.2023.031404
    Xia, S., Miao, Y., & Liu, S. (2018). Withaferin A induces apoptosis by ROS-dependent mitochondrial dysfunction in human colorectal cancer cells. Biochem Biophys Res Commun, 503(4), 2363-2369. https://doi.org/10.1016/j.bbrc.2018.06.162
    Xu, T., Ding, W., Ji, X., Ao, X., Liu, Y., Yu, W., & Wang, J. (2019). Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med, 23(8), 4900-4912. https://doi.org/10.1111/jcmm.14511
    Xu, X., Zhang, X., Wei, C., Zheng, D., Lu, X., Yang, Y., Luo, A., Zhang, K., Duan, X., & Wang, Y. (2020). Targeting SLC7A11 specifically suppresses the progression of colorectal cancer stem cells via inducing ferroptosis. Eur J Pharm Sci, 152, 105450. https://doi.org/10.1016/j.ejps.2020.105450
    Yan, H., Talty, R., Jain, A., Cai, Y., Zheng, J., Shen, X., Muca, E., Paty, P. B., Bosenberg, M. W., Khan, S. A., & Johnson, C. H. (2023). Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations. Redox Biol, 62, 102699. https://doi.org/10.1016/j.redox.2023.102699
    Yang, Y., Liu, L., Tian, Y., Gu, M., Wang, Y., Ashrafizadeh, M., Reza Aref, A., Canadas, I., Klionsky, D. J., Goel, A., Reiter, R. J., Wang, Y., Tambuwala, M., & Zou, J. (2024). Autophagy-driven regulation of cisplatin response in human cancers: Exploring molecular and cell death dynamics. Cancer Lett, 587, 216659. https://doi.org/10.1016/j.canlet.2024.216659
    Ye, X., Zhou, X. J., & Zhang, H. (2018). Exploring the Role of Autophagy-Related Gene 5 (ATG5) Yields Important Insights Into Autophagy in Autoimmune/Autoinflammatory Diseases. Front Immunol, 9, 2334. https://doi.org/10.3389/fimmu.2018.02334
    Zhang, X., Ma, Y., Ma, J., Yang, L., Song, Q., Wang, H., & Lv, G. (2022). Glutathione Peroxidase 4 as a Therapeutic Target for Anti-Colorectal Cancer Drug-Tolerant Persister Cells. Front Oncol, 12, 913669. https://doi.org/10.3389/fonc.2022.913669
    Zhang, Y., Tan, Y., Liu, S., Yin, H., Duan, J., Fan, L., Zhao, X., & Jiang, B. (2023). Implications of Withaferin A for the metastatic potential and drug resistance in hepatocellular carcinoma cells via Nrf2-mediated EMT and ferroptosis. Toxicol Mech Methods, 33(1), 47-55. https://doi.org/10.1080/15376516.2022.2075297
    Zhang, Z., Ji, Y., Hu, N., Yu, Q., Zhang, X., Li, J., Wu, F., Xu, H., Tang, Q., & Li, X. (2022). Ferroptosis-induced anticancer effect of resveratrol with a biomimetic nano-delivery system in colorectal cancer treatment. Asian J Pharm Sci, 17(5), 751-766. https://doi.org/10.1016/j.ajps.2022.07.006

    下載圖示
    QR CODE