IMR Press / FBL / Volume 24 / Issue 2 / DOI: 10.2741/4719

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article
Nobiletin sensitizes colorectal cancer cells to oxaliplatin by PI3K/Akt/MTOR pathway
Show Less
1 The Department of General Surgery, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, China
2 The Department of Oncology, Jing’an District Central Hospital of Shanghai, Fudan University, Shanghai, 200040, China
Front. Biosci. (Landmark Ed) 2019, 24(2), 303–312; https://doi.org/10.2741/4719
Published: 1 January 2019
(This article belongs to the Special Issue Leader sequences of coronavirus are altered during infection)
Abstract

Oxaliplatin is one of the most common chemotherapy drugs for colorectal cancer (CRC), but its application is greatly limited owing to the drug resistance. Nobiletin is a natural flavonoid isolated from citrus peel and has many biological functions, including anti-inflammatory, antitumor and neuroprotective activities. However, little is known about the effect of nobiletin on the anti-tumor activities of other chemotherapy drugs. In this study, we examined the effect of nobiletin on the efficacy of oxaliplatin in treatment of CRC by using two CRC cell lines. In vitro experiments indicated that nobiletin enhanced the inhibitory effect of oxaliplatin on the proliferation of CRC cells. Meanwhile, nobiletin promoted oxaliplatin-induced apoptosis of CRC cells, as demonstrated by the increased expression of pro-apoptotic proteins (Bax and cleaved-caspse3) and the down-regulation of anti-apoptotic protein Bcl-2. Mechanically, nobiletin sensitized CRC to oxaliplatin chemotherapy by down-regulating the PI3K/Akt/mTOR pathway. Taken together, our study has demonstrated that nobiletin could enhance the sensitivity of CRC to oxaliplatin chemotherapy, and provided a molecular basis for nobiletin’s potential applications in the chemosensitization of CRC.

Keywords
Colorectal cancer
Nobiletin
Oxaliplatin
Chemosensitization
2. INTRODUCTION

Colorectal cancer (CRC) is one of the most common malignancies worldwide. The diagnostic rate of CRC is ranked third in males and second in females, and the 5-year survival rate is relatively low compared with other types of cancer(1). Although surgery, new chemotherapeutic agents and targeted therapies have significantly reduced the mortality of CRC in the past 20 years, short-term tumor recurrence and drug resistance has greatly inhibited their further clinical applications(2,3). Oxaliplatin, one of the most effective drugs for CRC therapy, is a platinum-based chemotherapeutic agent that blocks DNA replication, leading to cell cycle arrest and cell death(4-7). It was reported that oxaliplatin significantly enhanced the survival rate of CRC patients(8-10). However, the decreased platinum influx, improved base excision repair, and increased detoxification, which lead to platinum resistance has largely debilitated the efficacy of oxaliplatin(4, 6). Thus, it is urgently needed to develop novel and effective therapeutic interventions to overcome oxaliplatin resistance.

Nobiletin is a polymethylated flavonoid extracted from the citrus peel of Citrus reticulata Blanco. Nobiletin has been reported to possess various biological effects, such as anti-inflammatory, anti-cancer and neuroprotective properties(11,12). Nobiletin exerts its anti-cancer activity in various cancers by inhibiting cell proliferation and angiogenesis and possibly leading to cell cycle arrest or apoptosis(13,14). However, the therapeutic effects of combinational nobiletin and chemotherapeutics on cancer have not been reported.

The PI3K/AKT/mTOR pathway plays a critical role in oncogenic process by regulating the proliferation, survival and metabolism of cancer cells(15-17). In addition, recent studies have demonstrated that inhibition of PI3K/AKT/mTOR signaling sensitized cancer cells to chemotherapeutics(18-20). Therefore, PI3K/AKT/mTOR signaling could be a potential target to search new chemosensitizers.

In this study, we examined the anti-tumor activity of nobiletin combined with oxaliplatin in CRC cells and explored its underlying mechanism. The results showed that nobiletin effectively sensitized CRC cells to oxaliplatin treatment by inhibiting proliferation and promoting apoptosis. Further study demonstrated that the chemosensitive effect of nobiletin was mediated by PI3K/AKT/mTOR signaling pathway.

3. MATERIALS AND METHODS
3. 1. Cell culture

HT29 and SW480 cells were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). Cells were cultured in DMEM complemented with FBS 10% (vol/vol; Life Technologies, Grand Island, USA) at 37°C in a 5% CO2 incubator.

3. 2. Cell viability assay

HT29 and SW480 cells were cultured on a 96-well plate and were treated with various doses of nobiletin and/or oxaliplatin. After 24 h of incubation, cell viability was measured by CCK-8 kit according to the manufacturer’s instruction (Beyotime Biotechnology, Shanghai, China).

3. 3. Flow cytometry

HT29 and SW480 cells were treated with oxaliplatin and different concentrations of nobiletin for 24 h. After washing with ice-cold PBS, cells were digested, centrifuged and stained with Annexin V-FITC and PI for 15min at room temperature. Cell apoptosis was then analyzed with a LSR-II flow cytometer.

3. 4. Western blot

Cells were lysed by RIPA Lysis Buffer (Shengxing Biotech, Nanjing, China). Equivalent amounts of protein sample were separated by 10% SDS-PAGE and transferred to a PVDF membrane (Millipore, Billerica, USA). After blocking with 5% non-fat dry milk, the membrane was then incubated with respectively primary antibodies and HRP-conjugated secondary antibodies (Abcam, Cambridge, MA). The blots were visualized by ECL and detected using ImageQuant LAS 4000 (Pittsburg, PA, USA).

3. 5. Statistical analysis

Data were analyzed by GraphPad Prism software and the results were expressed as mean ± standard deviation (SD). The statistical significance of the studies was analyzed using one way ANOVA. The difference was considered significant at P < 0.0.5.

4. RESULT
4. 1. Nobiletin decreases the viability of oxaliplatin-treated CRC cells

To gain insight into the anti-cancer activity of nobiletin, HT29 and SW480 cells were treated with various doses of nobiletin. As shown in Figure 1A and B, nobiletin significantly decreased the viability of CRC cells in a dose-dependent manner. In addition, the proliferation of CRC cells was markedly decreased after oxaliplatin treatment, and the inhibitory effect was further enhanced when combined with nobiletin (Figure 1C and D). These results suggest that nobiletin and oxaliplatin may act synergistically to enhance cytotoxicity in CRC cell lines.

Figure 1

Nobiletin decreases the viability of oxaliplatin-treated CRC cells. (A and B) HT29 (A) and SW480 (B) cells were treated with various doses of nobiletin (0-40 μM) for 24 h. Cell viabilities were measured by CCK-8 kit. (C and D) HT29 (C) and SW480 (D) cells were treated with oxaliplatin (5 μM) and/or 20-40 μM of nobiletin for 24 h. Cell viability were measured by CCK-8 kit. All the experiments were repeated at least three times. *P < 0.0.5 versus untreated control. #P < 0.0.5 versus oxaliplatin treated alone.

4. 2. Nobiletin promotes oxaliplatin-induced CRC cell apoptosis

To further investigate the effect of nobiletin on oxaliplatin-induced cell apoptosis, CRC cells were treated with oxaliplatin and nobiletin, and cell apoptosis was measured by flow cytometry. The results showed that nobiletin further enhanced the pro-apoptotic effect of oxaliplatin on CRC cells (Figure 2B). In addition, oxaliplatin combined with nobiletin significantly increased the expression of pro-apoptotic proteins (Bax and cleaved-caspase-3) and decreased the expression of anti-apoptotic protein (Bcl-2) in CRC cells when compared with oxaliplatin treated alone (Figure 2C-F). These results indicate that nobiletin promotes oxaliplatin-induced apoptosis of CRC cells.

Figure 2

Nobiletin promotes oxaliplatin-induced CRC cell apoptosis. HT29 and SW480 cells were treated with oxaliplatin (5 μM) and/or 20-40 μM of nobiletin for 24 h. (A) Cell apoptosis was analyzed by Annexin V flow cytometry. (B) Apoptotic cell quantification. (C and D) The expression of Bax, Bcl-2 and cleaved-caspase3 was measured by Western blot. (E and F) Quantification of Figure 2C and D. All the experiments were repeated at least three times. *P < 0.0.5 versus untreated control. #P < 0.0.5 versus oxaliplatin treated alone.

4. 3. Nobiletin promotes oxaliplatin-mediated down-regulation of PI3K/Akt/mTOR

The PI3K/AKT/mTOR signalling pathways is an important driver of CRC growth and progression. To further explore the mechanism underlying the chemosensitive effect of nobiletin, we examined the effect of nobiletin on PI3K/Akt/mTOR signaling. HT29 and SW480 cells were treated with oxaliplatin in presence or absence of nobiletin for 24 h, the phosphorylated Akt and mTOR were determined by Western blotting. The results showed that oxaliplatin increased the phosphorylation of Akt and mTOR, and this effect was augmented in the presence of nobiletin (Figure 3).

Figure 3

Nobiletin promotes oxaliplatin-mediated down-regulation of PI3K/Akt/mTOR. HT29 and SW480 cells were treated with oxaliplatin (5 μM) and/or 20-40 μM of nobiletin for 24 h. (A and C ) The phosphorylation of Akt and mTOR was detected by Western blot. (B and D) Quantification of Figure 3A and C. All the experiments were repeated at least three times. *P < 0.0.5 versus untreated control. #P <0.0.5 versus oxaliplatin treated alone.

4. 4. Nobiletin sensitizes CRC cells to oxaliplatin via down-regulating PI3K/Akt/mTOR pathway

To determine whether nobiletin inhibition of PI3K/AKT/mTOR contributes to its chemosensitization, IGF-1 was used to reactivate the PI3K signaling. HT29 and SW480 cells were treated with nobiletin and oxaliplatin in presence or absence of IGF-1 for 24 h. As shown in Figure 4A and 5A, IGF-1abolished the effect of nobiletin on cell viability in oxaliplatin-treated cells. Similarly, IGF-1 also reversed the inhibitory effect of nobiletin on cell apoptosis and apoptosis-related proteins in oxaliplatin-treated cells (Figure 4B-E, Figure 5B-E). Taken together, IGF-1 effectively inhibited the chemosensitization effect of nobiletin, indicating that nobiletin sensitizes CRC cells to oxaliplatin via down-regulating PI3K/Akt/mTOR pathway.

Figure 4

Nobiletin sensitizes CRC cells to oxaliplatin via down-regulating PI3K/Akt/mTOR pathway. HT29 cells, pretreated with or without nobiletin (40 μM) and/or IGF-1 (10 ng/ml), were incubated with oxaliplatin (5 μM) for 24 h. (A) Cell viability was measured by CCK-8 kit. (B) Cell apoptosis was analyzed by flow cytometry. (C) The expression of Bax, Bcl-2 and cleaved-caspase3 was measured by Western blot. (D and E) Quantification of Figure 4C. All the experiments were repeated at least three times. *P < 0.0.5, **P < 0.0.1 versus untreated control. #P < 0.0.5 versus oxaliplatin plus nobiletin.

Figure 5

Nobiletin sensitizes CRC cells to oxaliplatin via down-regulating PI3K/Akt/mTOR pathway. SW480 cells, pretreated with or without nobiletin (40 μM) and/or IGF-1 (10 ng/ml), were incubated with oxaliplatin (5 μM) for 24 h. (A) Cell viability was measured by CCK-8 kit. (B) Cell apoptosis was analyzed by flow cytometry. (C) The expression of Bax, Bcl-2 and cleaved-caspase3 was measured by Western blot. (D and E) Quantification of Figure 5C. All the experiments were repeated at least three times. *P < 0.0.5, **P < 0.0.1 versus untreated control. #P < 0.0.5 versus oxaliplatin plus nobiletin.

5. DISCUSSION

Chemotherapy is a mainstream anti-cancer therapy that effectively suppresses the growth of malignant tumors(21). It was reported that chemotherapeutic drugs are delivered to tumor by microcirculation. However, the maldistribution of drugs may lead to some specific changes of tumors in the microenvironment(22), including formation of hypoxic areas, elevation of interstitial fluid pressure and oligotrophy. These changes decrease the chemosensitivity of tumors and come about drug resistance(23). Thus, improving the drug resistance of cancer cells has become a research focus. Peng et al. have demonstrated that Astragaloside IV sensitizes non–small cell lung cancer cells to gefitinib via regulating of SIRT6(24). Ganji et al. have reported that HSP90 inhibition down-regulates thymidylate synthase and sensitizes colorectal cancer cell lines to 5FU(25). In this study, our results demonstrated that combined treatment with nobiletin could increase CRC cells response to oxaliplatin inhibition through PI3K/Akt/mTOR pathway.

Nobiletin has been shown to have anti-tumor activities in various types of cancer, such as gastric cancer, lung cancer and breast cancer(26-28), although its molecular mechanism remains unclear. In addition, recent studies showed that nobiletin sensitized cancer cells to chemotherapy. For example, nobiletin induces apoptosis and enhances the effects of the anticancer drug 5-fluorouracil in human gastric cancer cells(29). Co-treatment of nobiletin and atorvastatin displays a strong synergy in inhibiting colon carcinogenesis(30). Our results showed that nobiletin treated alone significantly decreased the proliferation of CRC cells at the dose of 100 and 200 μ?, which was consist with previous studies. Combined treatment with nobiletin increased the cytotoxicity of oxaliplatin on CRC cells, suggesting that nobiletin was capable of potentiating the anti-tumor activity of oxaliplatin.

The PI3K/Akt/mTOR signaling pathway is involved in various aspects of tumor progression, including cell proliferation, differentiation, survival, apoptosis, and metastasis(31,32), PI3K promotes tumor growth by activating mTOR. Akt inhibits cell apoptosis by up-regulating the phosphorylation of Bax and inactivating Bad(33). It was reported that mutations in the individual component of PI3K/Akt/mTOR signaling pathway account for as much as 30% of all known human cancers(34). Thus, many researchers have turned their focus on PI3K/Akt/mTOR pathway for treating cancer or enhancing chemotherapy sensitivity of cancer cells. For example, Guizhi Fuling Wan, a traditional Chinese herbal formula, sensitizes cisplatin-resistant Human ovarian cancer cells through inhibition of the PI3K/AKT/mTOR Pathway(35). Oxymatrine synergistically enhances the anti-tumor activity of oxaliplatin in colon carcinoma through PI3K/AKT/mTOR pathway(36) miRNA-7 increases cisplatin sensitivity of gastric cancer cells through suppressing mTOR(37). More importantly, PI3K/Akt signaling is also involved in the inhibitory effect of nobiletin on invasion and migration of cancer cells(11,12). In the present study, we found oxaliplatin inhibited the phosphorylation of Akt and mTOR, which was augmented in the presence of nobiletin. Gain-of-function study showed that nobiletin enhanced the anti-tumor effect of oxaliplatin through PI3K/Akt/mTOR pathway.

In conclusion, we found that nobiletin enhanced the anti-proliferative and apoptotic effect of oxaliplatin in CRC cells by modulating the PI3K/Akt/mTOR pathway. Since PI3K/Akt/mTOR signaling is involved in the pathogenesis of many types of cancer, our findings not only elaborate a novel mechanism of nobiletin’s chemosensitive effect, but also provide new insights into the combination of nobiletin and chemotherapeutic drugs in treatment CRC and other cancers.

6. ACKNOWLEDGEMENT

We sincerely appreciate the technical support from Beijing Luhe Hospital, Capital Medical University.

Abbreviations: CRC, Colorectal cancer; Bcl-2, B-cell lymphoma-2; Bax, Bcl-2 Associated X protein; PI3K/Akt/mTOR, Phosphatidyl inositol 3-kinase/Akt/ mammalian target of rapamycin; CCK-8, Cell Counting Kit 8; PI, Propidium iodide; IGF-1, Insulin-like growth factors-1.

References
[1]
JemalA, BrayF, CenterMM, FerlayJ, WardE, FormanD Global cancer statistics. CA Cancer J Clin 612 6990 201110.3322/caac.20107
[2]
Van CutsemE, NordlingerB, CervantesA Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol 21 Suppl59397 201010.1093/annonc/mdq222
[3]
TermeM, PernotS, MarcheteauE, SandovalF, BenhamoudaN, ColussiO, DubreuilO, CarpentierAF, TartourE, TaiebJ VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 732 539549 201310.1158/0008-5472.CAN-12-2325
[4]
KellandL The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer78:573584 200710.1038/nrc2167
[5]
MiyajimaA, NakashimaJ, YoshiokaK, TachibanaM, TazakiH, MuraiM Role of reactive oxygen species in cis-dichlorodiammineplatinum-induced cytotoxicity on bladder cancer cells. Br J Cancer762:206210 199710.1038/bjc.1997.363
[6]
LaurentA, NiccoC, ChereauC, GoulvestreC, AlexandreJ, AlvesA, LévyE, GoldwasserF, PanisY, SoubraneO, WeillB, BatteuxF Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res653:948956 2005
[7]
GodwinAK, MeisterA, O'DwyerPJ, HuangCS, HamiltonTC, AndersonME High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci U S A897:30703074 199210.1073/pnas.89.7.3070
[8]
Lievre A, Samalin E, Mitry E, Assenat E, Boyer-Gestin C, Lepere C, Bachet JB, Portales F, Vaillant JN, Ychou M, Rougier P Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study. BMC Cancer 9, 347 200910.1186/1471-2407-9-347
[9]
SeetharamR, SoodA, GoelS Oxaliplatin: pre-clinical perspectives on the mechanisms of action, response and resistance. Ecancermedicalscience 3, 153 2009
[10]
MaoL, LiY, ZhaoJ, LiQ, YangB, WangY, ZhuZ, SunH, ZhaiZ Transforming growth factor-beta1 contributes to oxaliplatin resistance in colorectal cancer via epithelial to mesenchymal transition. Oncol lett 141 647654 201710.3892/ol.2017.6209
[11]
ShiMD, LiaoYC, ShihYW, TsaiLY Nobiletin attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Phytomedicine 208, 743752 201310.1016/j.phymed.2013.02.004
[12]
LeeYC, ChengTH, LeeJS, ChenJH, LiaoYC, FongY, WuCH, ShihYW Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3K/Akt and small GTPase signals in human gastric adenocarcinoma AGS cells. Mol Cell Biochem 3471, 103115 201110.1007/s11010-012-1324-910.1007/s11010-010-0618-z
[13]
ChenJ, ChenAY, HuangH, YeX, RollysonWD, PerryHE, BrownKC, RojanasakulY, RankinGO, DasguptaP, ChenYC The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway. Int J Oncol 466 26292638 201510.3892/ijo.2015.2946
[14]
LamKH, AlexD, LamIK, TsuiSK, YangZF, LeeSM Nobiletin, a polymethoxylated flavonoid from citrus, shows anti-angiogenic activity in a zebrafish in vivo model and HUVEC in vitro model. J Cell Biochem 11211 33133321 201110.1002/jcb.23257
[15]
SilvestrisN, TommasiS, PetriellaD, SantiniD, FistolaE, RussoA, NumicoG, ToniniG, MaielloE, ColucciG The dark side of the moon: the PI3K/PTEN/AKT pathway in colorectal carcinoma. Oncology 77, Suppl16974 200910.1159/000258498
[16]
PanduranganAK Potential targets for prevention of colorectal cancer: a focus on PI3K/Akt/mTOR and Wnt pathways.
[17]
WangH, DuanL, ZouZ, LiH, YuanS, ChenX, ZhangY, LiX, SunH, ZhaH, ZhangY, ZhouL Activation of the PI3K/Akt/mTOR/p70S6K pathway is involved in S100A4-induced viability and migration in colorectal cancer cells. Int J Med Sci 118841849 201410.7150/ijms.8128
[18]
ShenZ, XuL, LiJ, ZhangN Capilliposide C Sensitizes Esophageal Squamous Carcinoma Cells to Oxaliplatin by Inducing Apoptosis Through the PI3K/Akt/mTOR Pathway. Med Sci Monit 23 20962103 201710.12659/MSM.901183
[19]
DaiC, ZhangB, LiuX, MaS, YangY, YaoY, FengM, BaoX, LiG, WangJ, GuoK, MaW, Asian Pac J Cancer Prev 144 22012205 2013 Xing B, Lian W, Xiao J, Cai F, Zhang H, Wang R Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice. Endocrinology 1543 12471259 201310.1210/en.2012-1908
[20]
YasumizuY, MiyajimaA, KosakaT, MiyazakiY, KikuchiE, OyaM Dual PI3K/mTOR inhibitor NVP-BEZ235 sensitizes docetaxel in castration resistant prostate cancer. J Urol1911:22734 201410.1016/j.juro.2013.07.101
[21]
SunY Tumor microenvironment and cancer therapy resistance. Cancer Lett 3801 205215 201610.1016/j.canlet.2015.07.044
[22]
FraczekN, BroniszI, PietrykaM, KepinskaD, StrzalaP, MielnickaK, KorgaA, DudkaJ An outline of main factors of drug resistance influencing cancer therapy. J Chemother 286 45764 201610.1080/1120009X.2016.1218158
[23]
RohwerN, CramerT Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat 143 191201 201110.1016/j.drup.2011.03.001
[24]
DaiPC, LiuDL, ZhangL, YeJ, WangQ, ZhangHW, LinXH, LaiGX Astragaloside IV sensitizes non-small cell lung cancer cells to gefitinib potentially via regulation of SIRT6. Tumour Biol 3941010428317697555 201710.1177/1010428317697555
[25]
NagarajuGP, AleseOB, LandryJ, DiazR, El-RayesBF HSP90 inhibition downregulates thymidylate synthase and sensitizes colorectal cancer cell lines to the effect of 5FU-based chemotherapy. Oncotarget 520 99809991 201410.18632/oncotarget.2484
[26]
DaC, LiuY, ZhanY, LiuK, WangR Nobiletin inhibits epithelial-mesenchymal transition of human non-small cell lung cancer cells by antagonizing the TGF-beta1/Smad3 signaling pathway. Oncol Rep 355 27672774 201610.3892/or.2016.4661
[27]
RahidehST, KeramatipourM, NourbakhshM, KoohdaniF, HoseiniM, ShidfarF The effects of Nobiletin, Hesperetin, and Letrozole in a combination on the activity and expression of aromatase in breast cancer cells. Cell Mol Biol 632 913 201710.14715/cmb/2017.63.2.2
[28]
MoonJY, ChoSK Nobiletin Induces Protective Autophagy Accompanied by ER-Stress Mediated Apoptosis in Human Gastric Cancer SNU-16 Cells. Molecules 217 piiE914. 201610.3390/molecules21070914
[29]
Moon JY, Cho M, Ahn KS, Cho SK Nobiletin induces apoptosis and potentiates the effects of the anticancer drug 5-fluorouracil in p53-mutated SNU-16 human gastric cancer cells. Nutr Cancer 652 28695 201310.1080/01635581.2013.756529
[30]
WuX, SongM, QiuP, RakariyathamK, LiF, GaoZ, CaiX, WangM, XuF, ZhengJ, XiaoH Synergistic chemopreventive effects of nobiletin and atorvastatin on colon carcinogenesis. Carcinogenesis 384 455464 201710.1093/carcin/bgx018
[31]
Golob-SchwarzlN, KrassnigS, ToeglhoferAM, ParkYN, Gogg-KamererM, VierlingerK, SchröderF, RheeH, SchichoR, FickertP, HaybaeckJ New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors. Eur J Cancer 83 5670 201710.1016/j.ejca.2017.06.003
[32]
EngelmanJA Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer98:550562 200910.1038/nrc2664
[33]
FletcherJI, HuangDC Controlling the cell death mediators Bax and Bak: puzzles and conundrums. Cell Cycle71:3944 200810.4161/cc.7.1.5178
[34]
AhmadA, BiersackB, LiY, KongD, BaoB, SchobertR, PadhyeSB, SarkarFH Targeted regulation of PI3K/Akt/mTOR/NF-kappaB signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy. Anticancer Agents Med Chem137:10021013 201310.4161/cc.7.1.5178
[35]
HanL, GuoX, BianH, YangL, ChenZ, ZangW, YangJ Guizhi Fuling Wan, a Traditional Chinese Herbal Formula, Sensitizes Cisplatin-Resistant Human Ovarian Cancer Cells through Inactivation of the PI3K/AKT/mTOR Pathway. Evid Based Complement Alternat Med 2016, 4651949 201610.14374/HFS.2016.24.3.195
[36]
LiuY, BiT, WangZ, WuG, QianL, GaoQ, ShenG Oxymatrine synergistically enhances antitumor activity of oxaliplatin in colon carcinoma through PI3K/AKT/mTOR pathway. Apoptosis 211213981407 201610.1007/s10495-016-1297-3
[37]
XuN, LianYJ, DaiX, WangYJ miR-7 Increases Cisplatin Sensitivity of Gastric Cancer Cells Through Suppressing mTOR. Technol Cancer Res Treat 1533034617717863 201710.1177/1533034617717863
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Share
Back to top