先前文獻報導葫蘆烷三萜類化合物透過延滯細胞週期及促進細胞凋亡而抑制乳癌、子宮頸癌及前列腺癌的增生，並且也能夠增強子宮頸癌細胞KB-V1對化療藥物vinblastine和paclitaxel的敏感度。關於3β, 7β, 25-trihydroxycucurbita-5, 23-dien-19-al (TCD)對於胃癌細胞之影響的文獻報告卻相當有限，因此本研究以人類AGS胃癌細胞模式，探討自山苦瓜葉萃取純化分離的TCD對於抑制胃癌細胞增殖和增強AGS細胞對於順鉑(cisplatin)敏感度的效應。
實驗結果顯示，由細胞存活率MTT分析及群落形成分析發現TCD (>20 µM) 單獨處理能顯著抑制AGS細胞增生與細胞聚落生成。由劉氏染色法觀察發現TCD改變AGS細胞的細胞核/細胞質比例和細胞型態，因此以流式細胞儀分析細胞凋亡(apoptotic assay)和細胞週期(cell cycle)，發現30 µM TCD會將細胞週期延滯於G1期並引致細胞凋亡。以西方轉漬法觀察發現30 µM TCD造成AGS細胞凋亡相關蛋白caspase 9、caspase 3、和PARP表現量上升。另外觀察caspase酵素活性發現30 µM TCD能提高AGS細胞caspase 3活性。為觀察TCD是否具有增強cisplatin的藥效，合併使用IC20濃度的TCD (20 µM)與cisplatin (2 µM) 有效抑制AGS細胞增生且具協同作用(synergism)。在核質比及細胞型態的部分，cisplatin會使細胞脹大、DNA斷裂溢出細胞核，TCD會使細胞核聚縮並死亡，TCD/cisplatin併用時AGS細胞兼具上述特質。TCD/cisplatin (20 µM/ 2 µM)併用時顯著增加AGS細胞的凋亡比例,並顯著抑制cisplatin誘導之TNF-α mRNA表現。
以AGS細胞異種移植模式，將裸鼠分為4組分別為控制組、TCD (20 mg/kg)組、cisplatin (4mg/kg)組和TCD/cisplatin併用組。給予藥物後經35天後觀察發現：和控制組比較，不論是單獨給予TCD或cisplatin和TCD/cisplatin併用都能顯著降低腫瘤體積和重量。於試驗第20~35天實驗期間TCD/cisplatin組的腫瘤體積平均值均低於其他3組，但僅於第30天和TCD組達統計上的顯著差異。然而投予TCD和TCD/cisplatin不會影響裸鼠體重和脾臟相對重量，但cisplatin組的體重和脾臟相對重量則顯著低於控制組和TCD組，因此推測TCD具有抑制AGS腫瘤生長的效用且副作用較低。
綜論，在細胞實驗TCD可透過延滯細胞週期、引起細胞凋亡和抑制細胞增生，導致AGS細胞存活率下降。當TCD與cisplatin併用具有協同性的抑制AGS增殖的效果。在動物實驗TCD能抑制AGS腫瘤生長，顯示TCD具有協助治療胃癌的潛力，未來仍有待更多的研究以了解TCD的抗腫瘤作用機制與化療藥物併用的效果。
關鍵字：胃癌、順鉑、三萜類化合物、抑制增殖、增強化療敏感

Cucurbitane-type triterpenoids exert chemopreventive effects and cytotoxicities toward several cancer cells, such as prostate, cervical, and breast cancers. Kuguacin J, one of cucurbitane-type triterpenoids isolated from bitter melon, improved the sensitivity of chemotherapy drugs in cervical cancer cells. However, the knowledge concerning the anti-tumor effect of 3β, 7β, 25-trihydroxycucurbita-5, 23-dien-19-al (TCD) is limited. In the present study, we investigated the anti-proliferative and chemosensitizing effects of TCD, isolated from leaves of wild bitter melon, on human AGS gastric adenocarcinoma cells.
AGS cells were treated with TCD alone or combined with cisplatin, a chemotherapeutic agent. Cell viability was assessed by MTT assay, cell cycle and apoptosis were assessed by flow-cytometric analysis, and the expression of major proteins regulating apoptosis was also detected. The results showed that TCD reduced cell viability, inhibited cell proliferation, and changed cellular morpgology of AGS cells. Flow cytometry revealed that TCD increased the sub-G1 population of of AGS cells. Treatment of TCD significantly increased caspase 3 activity. Western blotting showed that TCD treatment significantly increased the levels of pro-apoptotic proteins, including, caspase 9, caspase 3, and PARP, thus inducing apoptosis. It was also demonstrated that a combinational treatment of TCD and cisplatin synergistically inhibited cell growth and cisplatin-induced TNF-α expression, and increased apoptosis. Furthermore, a tumor xenograft model was generated by subcutaneous injection of AGS cells into the dorsum of nude mice. The growth of xenograft tumors was monitored and measured. Cisplatin (4mg/ kg·d), TCD (20 mg/ kg·d), or both combination significantly suppressed the tumor volume and weight from the 35th day after treatment, as compared to the vehicle control. However, the mice challenged with cisplatin showed body weight loss and splenic atrophy. No obvious damage to the organs was found in TCD group, indicating that TCD treatment (20 mg/ kg·d) showed no toxic effects. These findings suggested that the tumor-suppressing effect of TCD would be due to cell cycle inhibition, caspase activation and apotosis induction. TCD may be a promising candidate agent used in the treatment of gastric cancer.

Key word: gastric cancer, cisplatin, 3β, 7β, 25-trihydroxycucurbita-5, 23-dien-19-al, anti-proliferative and chemosensitizing effects

台灣癌症登記中心。http://tcr.cph.ntu.edu.tw/uploadimages/Survival_98_102.pdf。12/30/2016
全中和。2001。珍貴種源山苦瓜。花蓮區農業專訊，36 (6)，5-7。
全中和、林砡竹。(2008)。苦瓜新品種育成及 Gap 體系之建立。苦瓜產業與保健功效研討會刊，51-70。
國家衛生研究院。(2012)。胃癌臨床診療指引。
衛生福利部國民健康署。(2016)。中華民國102年癌症登記報告。
Aggarwal, B.B., Prasad, S., Reuter, S., Kannappan, R., Yadev, V.R., Park, B., Kim, J.H., Gupta, S.C., Phromnoi, K., & Sundaram, C. (2011). Identification of novel anti-inflammatory agents from Ayurvedic medicine for prevention of chronic diseases:“reverse pharmacology” and “bedside to bench” approach. Current drug targets, 12(11), 1595.
Agrawal, R., & Beohar, T. (2010). Chemopreventive and anticarcinogenic effects of Momordica charantia extract. Asian Pacific Journal of Cancer Prevention, 11(2), 371-375.
Ahn, H.J., & Lee, D.S. (2015). Helicobacter pylori in gastric carcinogenesis. World Journal of Gastrointestinal Oncology, 7(12), 455-465. doi: 10.4251/wjgo.v7.i12.455
Akihisa, T., Higo, N., Tokuda, H., Ukiya, M., Akazawa, H., Tochigi, Y., Kimura, Y., Suzuki, T., & Nishino, H. (2007). Cucurbitane-type triterpenoids from the fruits of Momordica charantia and their cancer chemopreventive effects. Journal of natural products, 70(8), 1233-1239.
Alghasham, A.A. (2013). Cucurbitacins–a promising target for cancer therapy. International journal of health sciences, 7(1).
Atmaca, A., Pauligk, C., Steinmetz, K., Altmannsberger, H.M., Jäger, E., & Al-Batran, S.E. (2011). Prognostic Impact of Phosphorylated Mitogen-Activated Protein Kinase Expression in Patients with Metastatic Gastric Cancer. Oncology, 80(1-2), 130-134.
Bai, L.Y., Chiu, C.F., Chu, P.C., Lin, W.Y., Chiu, S.J., & Weng, J.R. (2016). A triterpenoid from wild bitter gourd inhibits breast cancer cells. Sci Rep, 6, 22419. doi: 10.1038/srep22419
Bao, B., Chen, Y.-G., Zhang, L., Na Xu, Y.L., Wang, X., Liu, J., & Qu, W. (2013). Momordica charantia (Bitter Melon) Reduces Obesity-Associated Macrophage and Mast Cell Infiltration as well as Inflammatory Cytokine Expression in Adipose Tissues. PLOS ONE, 8(12), e84075. doi: 10.1371/journal.pone.0084075
Bárbara Peleteiro & Nuno Lunet (2011). Role of Genetic and Environmental Risk Factors in Gastric Carcinogenesis Pathway, Gastritis and Gastric Cancer - New Insights in Gastroprotection, Diagnosis and Treatments, Dr. Paola Tonino (Ed.), InTech
Chen, J.C., Chiu, M.H., Nie, R.L., Cordell, G.A., & Qiu, S.X. (2005). Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Rep, 22(3), 386-399. doi: 10.1039/b418841c
Cheng, H.L., Kuo, C.Y., Liao, Y.W., & Lin, C.C. (2012). EMCD, a hypoglycemic triterpene isolated from Momordica charantia wild variant, attenuates TNF-alpha-induced inflammation in FL83B cells in an AMP-activated protein kinase-independent manner. Eur J Pharmacol, 689(1-3), 241-248. doi: 10.1016/j.ejphar.2012.05.033
Cho, H.J., Baek, K.E., Park, S.-M., Kim, I.-K., Nam, I.-K., Choi, Y.-L., Park, S.-H., Im, M.-J., Choi, J., Ryu, J., Kim, J.W., Lee, C.W., Kang, S.S., & Yoo, J. (2011). RhoGDI2 confers gastric cancer cells resistance against cisplatin-induced apoptosis by upregulation of Bcl-2 expression. Cancer Letters, 311(1), 48-56. doi: http://dx.doi.org/10.1016/j.canlet.2011.06.024
Chun, J., Joo, E.J., Kang, M., & Kim, Y.S. (2013). Platycodin D induces anoikis and caspase-mediated apoptosis via p38 MAPK in AGS human gastric cancer cells. J Cell Biochem, 114(2), 456-470. doi: 10.1002/jcb.24386
Crew, K.D., & Neugut, A.I. (2006). Epidemiology of gastric cancer. World Journal of Gastroenterology, 12(3), 354. doi: 10.3748/wjg.v12.i3.354
Cui, W., Yazlovitskaya, E.M., Mayo, M.S., Pelling, J.C., & Persons, D.L. (2000). Cisplatin‐induced response of c‐jun N‐terminal kinase 1 and extracellular signal‐regulated protein kinases 1 and 2 in a series of cisplatin‐resistant ovarian carcinoma cell lines. Molecular carcinogenesis, 29(4), 219-228.
Dasari, S., & Tchounwou, P.B. (2014). Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol, 740, 364-378. doi: 10.1016/j.ejphar.2014.07.025
El-Senduny, F.F., Badria, F.A., EL-Waseef, A.M., Chauhan, S.C., & Halaweish, F. (2016). Approach for chemosensitization of cisplatin-resistant ovarian cancer by cucurbitacin B. Tumor Biology, 37(1), 685-698. doi: 10.1007/s13277-015-3773-8
Escandell, J.M., Recio, M.C., Máñez, S., Giner, R.M., Cerdá-Nicolás, M., & Ríos, J.L. (2007). Cucurbitacin R Reduces the Inflammation and Bone Damage Associated with Adjuvant Arthritis in Lewis Rats by Suppression of Tumor Necrosis Factor-α in T Lymphocytes and Macrophages. Journal of Pharmacology and Experimental Therapeutics, 320(2), 581-590. doi: 10.1124/jpet.106.107003
Fang, E.F., Zhang, C.Z.Y., Wong, J.H., Shen, J.Y., Li, C.H., & Ng, T.B. (2012a). The MAP30 protein from bitter gourd (Momordica charantia) seeds promotes apoptosis in liver cancer cells in vitro and in vivo. Cancer letters, 324(1), 66-74.
Fang, E.F., Zhang, C.Z.Y., Zhang, L., Fong, W.P., & Ng, T.B. (2012b). In vitro and in vivo anticarcinogenic effects of RNase MC2, a ribonuclease isolated from dietary bitter gourd, toward human liver cancer cells. The international journal of biochemistry & cell biology, 44(8), 1351-1360.
Fenoglio‐Preiser, C., Wang, J., Stemmermann, G., & Noffsinger, A. (2003). TP53 and gastric carcinoma: a review. Human mutation, 21(3), 258-270.
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. doi: 10.3390/cancers3011351
Freedman, N.D., Abnet, C.C., Leitzmann, M.F., Mouw, T., Subar, A.F., Hollenbeck, A.R., & Schatzkin, A. (2007). A prospective study of tobacco, alcohol, and the risk of esophageal and gastric cancer subtypes. Am J Epidemiol, 165(12), 1424-1433. doi: 10.1093/aje/kwm051
Fulda, S., & Debatin, K.-M. (2004). Sensitization for anticancer drug-induced apoptosis by the chemopreventive agent resveratrol. Oncogene, 23(40), 6702-6711.
Gomceli, I., Demiriz, B., & Tez, M. (2012). Gastric carcinogenesis. World J Gastroenterol, 18(37), 5164-5170.
Gu, K.-S., & Chen, Y. (2012). Mechanism of P-glycoprotein Expression in the SGC7901 Human Gastric Adenocarcinoma Cell Line Induced by Cyclooxygenase-2. Asian Pacific Journal of Cancer Prevention, 13(5), 2379-2383. doi: 10.7314/apjcp.2012.13.5.2379
Hsu, Tsai, T.-H., Li, Y.-Y., Wu, W.-H., Huang, C.-J., & Tsai, P.-J. (2012a). Wild bitter melon (Momordica charantia Linn. var. abbreviata Ser.) extract and its bioactive components suppress Propionibacterium acnes-induced inflammation. Food Chemistry, 135(3), 976-984. doi: http://dx.doi.org/10.1016/j.foodchem.2012.05.045
Hsu, H.Y., Lin, J.H., Li, C.J., Tsang, S.F., Tsai, C.H., Chyuan, J.H., Chiu, S.J., & Chuang, S.E. (2012b). Antimigratory Effects of the Methanol Extract from Momordica charantia on Human Lung Adenocarcinoma CL1 Cells. Evid Based Complement Alternat Med, 2012, 819632. doi: 10.1155/2012/819632
Isobe, T., Aoyagi, K., Koufuji, K., Shirouzu, K., Kawahara, A., Taira, T., & Kage, M. (2013). Clinicopathological significance of hypoxia-inducible factor-1 alpha (HIF-1α) expression in gastric cancer. International Journal of Clinical Oncology, 18(2), 293-304. doi: 10.1007/s10147-012-0378-8
Jayaprakasam, B., Seeram, N.P., & Nair, M.G. (2003). Anticancer and antiinflammatory activities of cucurbitacins from Cucurbita andreana. Cancer Lett, 189(1), 11-16.
Kaur, M., Deep, G., Jain, A.K., Raina, K., Agarwal, C., Wempe, M.F., & Agarwal, R. (2013). Bitter melon juice activates cellular energy sensor AMP-activated protein kinase causing apoptotic death of human pancreatic carcinoma cells. Carcinogenesis, 34(7), 1585-1592. doi: 10.1093/carcin/bgt081
Kaushik, U., Aeri, V., & Mir, S. (2015). Cucurbitacins - An insight into medicinal leads from nature. Pharmacognosy Reviews, 9(17), 12-18. doi: 10.4103/0973-7847.156314
Kelley, J.R., & Duggan, J.M. (2003). Gastric cancer epidemiology and risk factors. Journal of Clinical Epidemiology, 56(1), 1-9. doi: 10.1016/s0895-4356(02)00534-6
Kim, C.W., Lu, J.N., Go, S.I., Jung, J.H., Yi, S.M., Jeong, J.H., Hah, Y.S., Han, M.S., Park, J.W., Lee, W.S., & Min, Y.J. (2013). p53 restoration can overcome cisplatin resistance through inhibition of Akt as well as induction of Bax. Int J Oncol, 43(5), 1495-1502. doi: 10.3892/ijo.2013.2070
Kubola, J., & Siriamornpun, S. (2008). Phenolic contents and antioxidant activities of bitter gourd (Momordica charantia L.) leaf, stem and fruit fraction extracts in vitro. Food chemistry, 110(4), 881-890.
Kwatra, D., Dandawate, P., Padhye, S., & Anant, S. (2016). Bitter Melon as a Therapy for Diabetes, Inflammation, and Cancer: a Panacea? Current Pharmacology Reports, 2(1), 34-44. doi: 10.1007/s40495-016-0045-2
Kwatra, D., Subramaniam, D., Ramamoorthy, P., Standing, D., Moran, E., Velayutham, R., Mitra, A., Umar, S., & Anant, S. (2013). Methanolic extracts of bitter melon inhibit colon cancer stem cells by affecting energy homeostasis and autophagy. Evidence-Based Complementary and Alternative Medicine, 2013.
Lee-Huang, S., Huang, P.L., Sun, Y., Chen, H.C., Kung, H.F., & Murphy, W. (1999). Inhibition of MDA-MB-231 human breast tumor xenografts and HER2 expression by anti-tumor agents GAP31 and MAP30. Anticancer research, 20(2A), 653-659.
Lee, C.K., Park, K.K., Lim, S.S., Park, J.H., & Chung, W.Y. (2007). Effects of the licorice extract against tumor growth and cisplatin-induced toxicity in a mouse xenograft model of colon cancer. Biol Pharm Bull, 30(11), 2191-2195.
Lee, D.H., Iwanski, G.B., & Thoennissen, N.H. (2010). Cucurbitacin: ancient compound shedding new light on cancer treatment. ScientificWorldJournal, 10, 413-418. doi: 10.1100/tsw.2010.44
Leung, L., Birtwhistle, R., Kotecha, J., Hannah, S., & Cuthbertson, S. (2009). Anti-diabetic and hypoglycaemic effects of Momordica charantia (bitter melon): a mini review. British Journal of Nutrition, 102(12), 1703-1708.
Li, Tsang, S.F., Tsai, C.H., Tsai, H.Y., Chyuan, J.H., & Hsu, H.Y. (2012a). Momordica charantia Extract Induces Apoptosis in Human Cancer Cells through Caspase- and Mitochondria-Dependent Pathways. Evid Based Complement Alternat Med, 2012, 261971. doi: 10.1155/2012/261971
Li, D., Zhang, Y., Xie, Y., Xiang, J., Zhu, Y., & Yang, J. (2013). Enhanced tumor suppression by adenoviral PTEN gene therapy combined with cisplatin chemotherapy in small-cell lung cancer. Cancer gene therapy, 20(4), 251-259.
Li, M., Chen, Y., Liu, Z., Shen, F., Bian, X., & Meng, Y. (2009). Anti-tumor activity and immunological modification of ribosome-inactivating protein (RIP) from Momordica charantia by covalent attachment of polyethylene glycol. Acta Biochimica et Biophysica Sinica, 41(9), 792-799. doi: 10.1093/abbs/gmp068
Li, Y., Tan, B., Zhao, Q., Fan, L.-Q., Liu, Y., Hao, Y.-J., & Zhao, X.-F. (2012b). Tumor chemosensitivity is correlated with expression of multidrug resistance associated factors in variously differentiated gastric carcinoma tissues. Hepato-gastroenterology, 60(121), 213-216.
Lii, C.-K., Chen, H.-W., Yun, W.-T., & Liu, K.-L. (2009). Suppressive effects of wild bitter gourd (Momordica charantia Linn. var. abbreviata ser.) fruit extracts on inflammatory responses in RAW 264.7 macrophages. Journal of Ethnopharmacology, 122(2), 227-233. doi: http://dx.doi.org/10.1016/j.jep.2009.01.028
Lin, Y., Shi, R., Wang, X., & Shen, H.-M. (2008). Luteolin, a flavonoid with potentials for cancer prevention and therapy. Current cancer drug targets, 8(7), 634-646.
Liu, Zhang, M., Zhang, H., Sun, C., Yang, X., Deng, Y., & Ji, W. (2008a). Combined antitumor activity of cucurbitacin B and docetaxel in laryngeal cancer. Eur J Pharmacol, 587(1-3), 78-84. doi: 10.1016/j.ejphar.2008.03.032
Liu, F.S. (2009). Mechanisms of chemotherapeutic drug resistance in cancer therapy--a quick review. Taiwan J Obstet Gynecol, 48(3), 239-244. doi: 10.1016/s1028-4559(09)60296-5
Liu, L., Ning, X., Sun, L., Zhang, H., Shi, Y., Guo, C., Han, S., Liu, J., Sun, S., & Han, Z. (2008b). Hypoxia‐inducible factor‐1α contributes to hypoxia‐induced chemoresistance in gastric cancer. Cancer science, 99(1), 121-128.
Liu, T., Peng, H., Zhang, M., Deng, Y., & Wu, Z. (2010). Cucurbitacin B, a small molecule inhibitor of the Stat3 signaling pathway, enhances the chemosensitivity of laryngeal squamous cell carcinoma cells to cisplatin. European Journal of Pharmacology, 641(1), 15-22. doi: 10.1016/j.ejphar.2010.04.062
Mayne, S.T., Risch, H.A., Dubrow, R., Chow, W.-H., Gammon, M.D., Vaughan, T.L., Farrow, D.C., Schoenberg, J.B., Stanford, J.L., & Ahsan, H. (2001). Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiology Biomarkers & Prevention, 10(10), 1055-1062.
Miller, R.P., Tadagavadi, R.K., Ramesh, G., & Reeves, W.B. (2010). Mechanisms of Cisplatin nephrotoxicity. Toxins (Basel), 2(11), 2490-2518. doi: 10.3390/toxins2112490
Mimori, K., Sadanaga, N., Yoshikawa, Y., Ishikawa, K., Hashimoto, M., Tanaka, F., Sasaki, A., Inoue, H., Sugimachi, K., & Mori, M. (2006). Reduced tau expression in gastric cancer can identify candidates for successful Paclitaxel treatment. British journal of cancer, 94(12), 1894-1897.
Nam, S.Y., Lee, H.S., JUNG, G.A., Choi, J., Cho, S.J., Kim, M.K., Kim, W.H., & Lee, B.L. (2003). Akt/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis. Apmis, 111(12), 1105-1113.
Nerurkar, P.V., Lee, Y.-K., & Nerurkar, V.R. (2010). Momordica charantia (bitter melon) inhibits primary human adipocyte differentiation by modulating adipogenic genes. BMC complementary and alternative medicine, 10(1), 1.
Nerurkar, P.V., Lee, Y.K., Motosue, M., Adeli, K., & Nerurkar, V.R. (2008). Momordica charantia (bitter melon) reduces plasma apolipoprotein B-100 and increases hepatic insulin receptor substrate and phosphoinositide-3 kinase interactions. Br J Nutr, 100(4), 751-759. doi: 10.1017/S0007114508937430
Nerurkar, P.V., Pearson, L., Efird, J.T., Adeli, K., Theriault, A.G., & Nerurkar, V.R. (2005). Microsomal triglyceride transfer protein gene expression and ApoB secretion are inhibited by bitter melon in HepG2 cells. J Nutr, 135(4), 702-706.
Ohta, T., Ohmichi, M., Hayasaka, T., Mabuchi, S., Saitoh, M., Kawagoe, J., Takahashi, K., Igarashi, H., Du, B., & Doshida, M. (2006). Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models. Endocrinology, 147(4), 1761-1769.
Oki, E., Baba, H., Tokunaga, E., Nakamura, T., Ueda, N., Futatsugi, M., Mashino, K., Yamamoto, M., Ikebe, M., Kakeji, Y., & Maehara, Y. (2005). Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. International Journal of Cancer, 117(3), 376-380. doi: 10.1002/ijc.21170
Peek, R.M., & Blaser, M.J. (2002). Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer, 2(1), 28-37.
Petronelli, A., Pannitteri, G., & Testa, U. (2009). Triterpenoids as new promising anticancer drugs. Anti-Cancer Drugs, 20(10), 880-892. doi: 10.1097/CAD.0b013e328330fd90
Pitchakarn, Ogawa, K., Suzuki, S., Takahashi, S., Asamoto, M., Chewonarin, T., Limtrakul, P., & Shirai, T. (2010). Momordica charantia leaf extract suppresses rat prostate cancer progression in vitro and in vivo. Cancer science, 101(10), 2234-2240.
Pitchakarn, Suzuki, S., Ogawa, K., Pompimon, W., Takahashi, S., Asamoto, M., Limtrakul, P., & Shirai, T. (2011). Induction of G1 arrest and apoptosis in androgen-dependent human prostate cancer by Kuguacin J, a triterpenoid from Momordica charantia leaf. Cancer Lett, 306(2), 142-150. doi: 10.1016/j.canlet.2011.02.041
Pitchakarn, Suzuki, S., Ogawa, K., Pompimon, W., Takahashi, S., Asamoto, M., Limtrakul, P., & Shirai, T. (2012a). Kuguacin J, a triterpeniod from Momordica charantia leaf, modulates the progression of androgen-independent human prostate cancer cell line, PC3. Food Chem Toxicol, 50(3-4), 840-847. doi: 10.1016/j.fct.2012.01.009
Pitchakarn, P., Ohnuma, S., Pintha, K., Pompimon, W., Ambudkar, S.V., & Limtrakul, P. (2012b). Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance. J Nutr Biochem, 23(1), 76-84. doi: 10.1016/j.jnutbio.2010.11.005
Prestayko, A.W. (2013). Cisplatin: Current Status and New Developments: Elsevier Science.
Raman, A., & Lau, C. (1996). Anti-diabetic properties and phytochemistry of Momordica charantia L. (Cucurbitaceae). Phytomedicine, 2(4), 349-362. doi: http://dx.doi.org/10.1016/S0944-7113(96)80080-8
Ray, R.B., Raychoudhuri, A., Steele, R., & Nerurkar, P. (2010). Bitter melon (Momordica charantia) extract inhibits breast cancer cell proliferation by modulating cell cycle regulatory genes and promotes apoptosis. Cancer Research, 70(5), 1925-1931.
Rohwer, N., Dame, C., Haugstetter, A., Wiedenmann, B., Detjen, K., Schmitt, C.A., & Cramer, T. (2010). Hypoxia-Inducible Factor 1α Determines Gastric Cancer Chemosensitivity via Modulation of p53 and NF-κB. PLOS ONE, 5(8), e12038. doi: 10.1371/journal.pone.0012038
Sadzuka, Y., Hatakeyama, H., Daimon, T., & Sonobe, T. (2008). Screening of biochemical modulator by tumor cell permeability of doxorubicin. International journal of pharmaceutics, 354(1), 63-69.
Sathishsekar, D., & Subramanian, S. (2005). Antioxidant properties of Momordica Charantia (bitter gourd) seeds on Streptozotocin induced diabetic rats. Asia Pacific journal of clinical nutrition, 14(2), 153.
Seo, C.-R., Yang, D.K., Song, N.-J., Yun, U.J., Gwon, A.R., Jo, D.-G., Cho, J.Y., Yoon, K., Ahn, J.-Y., Nho, C.W., Park, W.J., Yang, S.Y., & Park, K.W. (2014). Cucurbitacin B and cucurbitacin I suppress adipocyte differentiation through inhibition of STAT3 signaling. Food and Chemical Toxicology, 64, 217-224. doi: http://dx.doi.org/10.1016/j.fct.2013.11.040
Sethi, G., Ahn, K.S., Pandey, M.K., & Aggarwal, B.B. (2007). Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB–regulated gene products and TAK1-mediated NF-κB activation. Blood, 109(7), 2727-2735.
Shi, W.J., & Gao, J.B. (2016). Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol, 8(9), 673-681. doi: 10.4251/wjgo.v8.i9.673
Shih, C.-C., Lin, C.-H., & Lin, W.-L. (2008). Effects of Momordica charantia on insulin resistance and visceral obesity in mice on high-fat diet. Diabetes Research and Clinical Practice, 81(2), 134-143. doi: http://dx.doi.org/10.1016/j.diabres.2008.04.023
Singh, D.K., Upadhyay, A., & Agrahari, P. (2015). A Review on Salient Pharmacological Features of Momordica charantia. International Journal of Pharmacology, 11(5), 405-413. doi: 10.3923/ijp.2015.405.413
Somasagara, R.R., Deep, G., Shrotriya, S., Patel, M., Agarwal, C., & Agarwal, R. (2015). Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells. Int J Oncol, 46(4), 1849-1857. doi: 10.3892/ijo.2015.2885
Subbaramaiah, K., Michaluart, P., Sporn, M.B., & Dannenberg, A.J. (2000). Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Cancer research, 60(9), 2399-2404.
Sun, L., Liu, L., Liu, X., Wang, Y., Li, M., Yao, L., Yang, J., Ji, G., Guo, C., & Pan, Y. (2014a). Gastric cancer cell adhesion to laminin enhances acquired chemotherapeutic drug resistance mediated by MGr1-Ag/37LRP. Oncology reports, 32(1), 105-114.
Sun, L., Liu, L., Liu, X., Wang, Y., Li, M., Yao, L., Yang, J., Ji, G., Guo, C., & Pan, Y. (2014b). MGr1‐Ag/37LRP induces cell adhesion‐mediated drug resistance through FAK/PI3K and MAPK pathway in gastric cancer. Cancer science, 105(6), 651-659.
Svobodova, B., Barros, L., Calhelha, R.C., Heleno, S., Alves, M.J., Walcott, S., Bittova, M., Kuban, V., & Ferreira, I.C.F.R. (2017). Bioactive properties and phenolic profile of Momordica charantia L. medicinal plant growing wild in Trinidad and Tobago. Industrial Crops and Products, 95, 365-373. doi: 10.1016/j.indcrop.2016.10.046
Tamanoi, F., & Bathaie, S. Z. (2014). Natural products and cancer signaling: isoprenoids, polyphenols and flavonoids (Vol. 36). Academic Press.
Tan, M.J., Ye, J.M., Turner, N., Ke, C.Q., Tang, C.P., Chen, T., Hohnen-Behrens, C., Rowland, A., James, D.E., & Ye, Y. (2008). New Cucurbitane triterpenoids from bitter melon with potent antidiabetic properties associated with activation of AMPK. Planta Med, 74(09), SL30. doi: 10.1055/s-0028-1083910
Tan, W., Yu, H.-G., & Luo, H.-S. (2014). Inhibition of the p38 MAPK pathway sensitizes human gastric cells to doxorubicin treatment in vitro and in vivo. Molecular medicine reports, 10(6), 3275-3281.
Thoennissen, N.H., Iwanski, G.B., Doan, N.B., Okamoto, R., Lin, P., Abbassi, S., Song, J.H., Yin, D., Toh, M., Xie, W.D., Said, J.W., & Koeffler, H.P. (2009). Cucurbitacin B induces apoptosis by inhibition of the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells. Cancer Res, 69(14), 5876-5884. doi: 10.1158/0008-5472.CAN-09-0536
Tian, Z., Yang, M., Huang, F., Li, K., Si, J., Shi, L., Chen, S., & Xiao, P. (2005). Cytotoxicity of three cycloartane triterpenoids from Cimicifuga dahurica. Cancer Lett, 226(1), 65-75. doi: 10.1016/j.canlet.2004.11.019
Tsai, T.-H., Huang, W.-C., Ying, H.-T., Kuo, Y.-H., Shen, C.-C., Lin, Y.-K., & Tsai, P.-J. (2016). Wild Bitter Melon Leaf Extract Inhibits Porphyromonas gingivalis-Induced Inflammation: Identification of Active Compounds through Bioassay-Guided Isolation. Molecules, 21(4), 454.
Vyas, D., Laput, G., & Vyas, A.K. (2014). Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Onco Targets Ther, 7, 1015-1023. doi: 10.2147/OTT.S60114
Wang, X., Sun, W., Cao, J., Qu, H., Bi, X., & Zhao, Y. (2012). Structures of new triterpenoids and cytotoxicity activities of the isolated major compounds from the fruit of Momordica charantia L. J Agric Food Chem, 60(15), 3927-3933. doi: 10.1021/jf204208y
Washington, K. (2010). 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol, 17(12), 3077-3079. doi: 10.1245/s10434-010-1362-z
Weng, J.-R., Bai, L.-Y., Chiu, C.-F., Hu, J.-L., Chiu, S.-J., & Wu, C.-Y. (2013). Cucurbitane triterpenoid from Momordica charantia induces apoptosis and autophagy in breast cancer cells, in part, through peroxisome proliferator-activated receptor γ activation. Evidence-Based Complementary and Alternative Medicine, 2013.
Wu, S.-J., & Ng, L.-T. (2008). Antioxidant and free radical scavenging activities of wild bitter melon (Momordica charantia Linn. var. abbreviata Ser.) in Taiwan. LWT - Food Science and Technology, 41(2), 323-330. doi: 10.1016/j.lwt.2007.03.003
Xiong, S.D., Yu, K., Liu, X.H., Yin, L.H., Kirschenbaum, A., Yao, S., Narla, G., DiFeo, A., Wu, J.B., & Yuan, Y. (2009). Ribosome‐inactivating proteins isolated from dietary bitter melon induce apoptosis and inhibit histone deacetylase‐1 selectively in premalignant and malignant prostate cancer cells. International journal of cancer, 125(4), 774-782.
Xu, H.-Y., Xu, W.-L., Wang, L.-Q., Chen, M.-B., & Shen, H.-L. (2014). Relationship between p53 status and response to chemotherapy in patients with gastric cancer: a meta-analysis. PloS one, 9(4), e95371.
Yadav, V.R., Prasad, S., Sung, B., Kannappan, R., & Aggarwal, B.B. (2010). Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer. Toxins (Basel), 2(10), 2428-2466. doi: 10.3390/toxins2102428
Yamaguchi, K., Ishikawa, T., Kondo, Y., & Fujisawa, M. (2008). Cisplatin regulates Sertoli cell expression of transferrin and interleukins. Mol Cell Endocrinol, 283(1-2), 68-75. doi: 10.1016/j.mce.2007.11.021
Yin, D., Wakimoto, N., Xing, H., Lu, D., Huynh, T., Wang, X., Black, K.L., & Koeffler, H.P. (2008). Cucurbitacin B markedly inhibits growth and rapidly affects the cytoskeleton in glioblastoma multiforme. Int J Cancer, 123(6), 1364-1375. doi: 10.1002/ijc.23648
Yu, D.-f., Wu, F.-r., Liu, Y., Liu, H., & Xia, Q. (2013). Bcl-2 gene silence enhances the sensitivity toward 5-Fluorouracil in gastric adenocarcinoma cells. Biomedicine & Pharmacotherapy, 67(7), 615-619. doi: http://dx.doi.org/10.1016/j.biopha.2013.03.007
Yung, M.M., Ross, F.A., Hardie, D.G., Leung, T.H., Zhan, J., Ngan, H.Y., & Chan, D.W. (2015). Bitter Melon (Momordica charantia) Extract Inhibits Tumorigenicity and Overcomes Cisplatin-Resistance in Ovarian Cancer Cells Through Targeting AMPK Signaling Cascade. Integr Cancer Ther. doi: 10.1177/1534735415611747
Zhang, Zhang, J., Shen, L., Xu, X.-m., & Yu, H.-g. (2013). Overexpression of AKT decreases the chemosensitivity of gastric cancer cells to cisplatin in vitro and in vivo. Molecular medicine reports, 7(5), 1387-1390.
Zhang, C.Z., Fang, E.F., Zhang, H.T., Liu, L.L., & Yun, J.P. (2015). Momordica charantia lectin exhibits antitumor activity towards hepatocellular carcinoma. Invest New Drugs, 33(1), 1-11. doi: 10.1007/s10637-014-0156-8