Stat3 蛋白與癌症息息相關。抑制Stat3可降低「非小細胞肺癌」細胞的存活並促使細胞死亡。我們也發現，Stat3的活化會對化學治療產生抗藥性（如：paclitaxel, 太平洋紫杉醇）。太平洋紫杉醇是個治療肺癌的重要藥物，它可引發MAPK的訊息傳遞使細胞死亡，但它亦可引發其他的訊息，如：NF-κB及AP-1 pathway，而讓癌細胞存活(Cancer Immunol Immunother 49:78-84, 2000)。
許多化學治療（如：太平洋紫杉醇）都會產生自由基 (Reactive Oxygen Species, ROS)。ROS會活化許多訊息傳遞，讓癌細胞對化學治療產生較易死亡或是讓癌細胞較有抗藥性（如：NF-κB、AP-1、Jak/Stat3 pathway）。另外，癌細胞的粒線體所產生的ROS的量，也與粒線體的Uncoupling Protein 2 (UCP-2)蛋白有關。在大腸癌的致癌過程中，UCP-2蛋白會逐漸增加，同時UCP-2蛋白的增加會減少自由基的產生(Carcinogenesis 2006;27:956-61)。至於癌細胞的UCP-2蛋白的多寡如何去影響癌細胞對化療藥物所產生的ROS之生物效應，則仍屬未知。
在我們的研究中發現，有些肺癌細胞（如：A549、H460 及CL1-0細胞），其UCP-2蛋白表現量多，則如：太平洋紫杉醇及順鉑 (Cisplatin)等化療藥物，就不會引發太多的ROS。反之，在UCP-2蛋白表現量少的細胞中（如：AS2 、H157及CL1-5細胞），化學治療會刺激較多的ROS產生，而活化Jak2/Stat3/Survivin(Mcl-1)訊息，導致癌細胞對化學藥物產生抗藥性。另外，在晚期肺癌，第一線即使用含順鉑的化學治療的病人，若其癌細胞的UCP-2蛋白表現量多，他們對化學治療的反應較佳且具有較好的存活。因此，在UCP-2蛋白表現量少的細胞中，若能用藥物去抑制化療藥物所引發ROS-Stat3活化訊息的產生，最後將可提升化學治療的效果。
既然Stat3的活化會對化學治療產生抗藥性，因此Stat3是一個我們克服抗藥性的一個標的。目前我們可以利用小分子的抑制劑(small molecule inhibitors) 或是用siRNA，去抑制Stat3蛋白。雖Stat3 siRNA具有「容易設計」、「高專一性」及「效果佳」等優點，但它也有「在體內易被酵素分解」的缺點及「藥物動力學」的問題，故臨床上並未被大量使用。
目前我們已能合成「可同時攜帶「太平洋紫杉醇」及Stat3 siRNA」的PLGA的奈米粒子，以改善癌症的治療效果。因為FDA已通過PLGA 『 (Poly-D, L-lactide-co-glycolide acid) 』的材質運用在醫學上，因為它有「生物分解」 (biodegradable)、「生物相容」 (biocompatible)，及較無毒性的特性。「奈米」粒子 也可攜帶siRNA。同時，攜帶抗癌藥物的「奈米」粒子已被證明可突破MDR (multi-drug resistance g-glycoprotein)相關的抗藥性，增加抗癌效果。
在肺癌細胞株A549及A549所衍生出對「太平洋紫杉醇」有抗藥性的T12細胞-（因T12細胞的α tubulin產生突變）， PLGA奈米攜帶著太平洋紫杉醇，相較於單獨的太平洋紫杉醇而言，有極佳毒殺A549及T12細胞之效果。另外當PLGA攜帶著太平洋紫杉醇後，其表面包裹著帶有正電荷的polyethylenimine (PEI)；接著此PEI即可利用「電力相吸」的原理，吸引帶有負電荷的Stat3 siRNA，形成可以同時攜帶著太平洋紫杉醇 及Stat3 siRNA的PLGA nanocomplex。此一nanocomplex，可順利進入A549及T12細胞，並降低Stat3的表現。同時，比起單獨太平洋紫杉醇來說，更能使tubulin蛋白聚集，也更能引起細胞死亡。
雖然肺癌細胞都具有活化的Stat3蛋白表現，透過化學治療與癌細胞UCP-2蛋白的交互作用，讓ROS對癌細胞的「一刀兩面」的效應。在太平洋紫杉醇及順鉑刺激下，我們可以去偵測癌細胞是「Stat3蛋白活化」或「Stat3去蛋白活化」。若為「Stat3蛋白活化」，則癌細胞是歸類為「低UCP-2蛋白表現量」的癌細胞；反之，若為「Stat3蛋白去活化」，則癌細胞是歸類為「高UCP-2蛋白表現量」的癌細胞。
我們已可在UCP-2蛋白表現量高的細胞中，利用Genipin的藥物可抑制UCP-2的表現，讓化學治療所產生「ROS」增加，進而加速癌細胞的死亡。在UCP-2蛋白表現量低的細胞中，用「ROS 抑制劑」可阻斷化學治療所產生的「ROS-細胞存活」的訊息傳遞，而讓細胞死亡。將來將針對不同UCP-2蛋白表現的癌細胞，我們有不同的治療策略，有效的毒殺癌細胞，提升治療效果。

Stat3 is more involved in tumor formation and Stat3 inhibition results in reduced cell viability and increased apoptosis in Non-Small Cell Lung Cancer (NSCLC). We have demonstrated that lung cancer cells with constitutive Stat3 activation are more resistant to paclitaxel-induced death. Besides, paclitaxel activates components of the mitogen-activated protein kinase (MAPK) signaling cascade to induce cellular apoptosis. Paclitaxel also stimulates NF-κB and activator protein 1 (AP-1) to promote cell proliferation (Cancer Immunol Immunother 49:78-84, 2000).
Many anticancer agents, including paclitaxel, have been reported to generate reactive oxygen species (ROS). ROS have a dual role in cancer chemotherapy efficacy - make cancer cells either more sensitive or resistant to anticancer drugs. ROS may cause constitutive activation of transcription factors, such as NF-κB, AP-1, and Jak/Stat3, to promote cellular proliferation. Besides, increase in UCP-2 expression is to decrease ROS generation, which may contribute to the carcinogenesis of human colon cancer. However, the relationship between the UCP-2 expression and cellular response to chemotherapy-induced oxidative stress has not been well studied.
In our study, we found that different human lung cancer cells have different UCP-2 expression. A549, H460 cells and CL1-0 cells expressed higher levels of UCP-2 protein. Paclitaxel did not induce higher levels of mitochondria-derived ROS in them; when UCP-2 was downregulated, paclitaxel might re-induce much ROS to induce cell death. On the contrary, in cancer cells with less UCP-2 expression as in AS2, H157 and CL1-5 cells, paclitaxel may induce ROS to activate Stat3/survivin/Mcl-1, thereby allowing the cancer cells to evade apoptosis. Besides, in lung cancer patients, low UCP-2 expression in cancer cells was also a predictor of a poor response to chemotherapy and had poor survival. In lower UCP-2 expression cancer cells, inhibition of ROS/Stat3 pathway may enhance treatment efficacy.
Currently, “siRNAs” and small molecules to inhibit cellular signaling are used to inhibit a specific gene expression. siRNAs are easy to design and have high target selectivity and have a good effect on suppression of gene expression, but they have not performed in the clinic because they are easily degraded by nucleases and their poor pharmacokinetic profile. The FDA approved poly (D, L)-lactide-co-glycolide acid (PLGA) for clinical use in humans because it is biodegradable, biocompatible, and only mildly toxic. Nanoparticles (NPs) can deliver siRNA; besides, nanoparticles (NPs) carrying agents is proved as a vector to overcome chemoresistance related to MDR protein. Since Stat3 activation contributes cellular resistance to paclitaxel, nanoparticles simultaneously delivering Stat3 siRNA and paclitaxel are a useful way to down-regulate Stat3 expression to overcome chemoresistance to paclitaxel.
In A549 and A549-derived paclitaxel resistant T12 cells with α tubulin mutation, PLGA NPs delivering paclitaxel are more cytotoxic to cancer cells than pclitaxel alone. To successfully synthesize the PLGA nanocomplex (PLGA-paclitaxel-Stat3 siRNA); first, paclitaxel was encapsulated by PLGA NPs (PLGA-TAX). The surfaces of PLGA-TAX were coated with polyethylenimine (PEI) (PLGA-TAX-PEI). Then, negative charge of siRNA was carried onto the surface of the PLGA NPs by electric attraction of positive charge of PEI (PLGA-TAX-PEI-S3SI). This PLGA-TAX-PEI-S3SI was uptaken into A549 and T12 cells and suppressed intracellular Stat3 expression. Compared to paclitaxel alone, the PLGA nanocomplex can make cellular tubulin more aggregation and were more cytotoxic to the cancer cells.
Although lung cancer cells possess constitutively activated Stat3, paclitaxel either activates or suppresses Stat3 activation after chemotherapy through UCP-2-mediated ROS production. In high UCP-2 expression cancer cells where paclitaxel/cisplatin suppresses Stat3 activation, inhibition of UCP-2 with genipin (a derive from plant) can overcome chemoresistance through enhanced ROS-mediated cytotoxic effect; in lower UCP-2 expression cancer cells where paclitaxel/cisplatin activates Stat3, ROS inhibitor can interrupt ROS-induced cellular survival signaling by chemotherapy, which leads to cancer cells death. Therefore in the future, we may use different agents (either UCP-2 inhibitor or ROS scavenger) to enhance treatment efficacy according to cellular UCP-2 expression.

Ajabnoor GM, Crook T, Coley HM. Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells. Cell Death Dis. 3: e260, 2012.
Alexandre J. Batteux F, Nicco C, Chéreau C, Laurent A, Guillevin L, Weill B, Goldwasser F. Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo. Int. J. Cancer, 119: 41-48, 2006.
Alexandre J, Hu Y, Lu W, Pelicano H, Huang P. Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species. Cancer Res. 67: 3512-3517, 2007.
Alley MC. Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 48: 589-601, 1988.
Azarmi S, Roa WH, Löbenberg R. Targeted delivery of nanoparticles for the treatment of lung diseases. Adv Drug Deliv Rev. 60: 863-875, 2008.
Baffy G. Uncoupling protein-2 and cancer. Mitochondrion 10: 243-252, 2010.
Basu Ball W, Kar S, Mukherjee M, Chande AG, Mukhopadhyaya R, Das PK. Uncoupling protein 2 negatively regulates mitochondrial reactive oxygen species generation and induces phosphatase-mediated anti-inflammatory response in experimental visceral leishmaniasis. J. Immunol 187: 1322-1332, 2011.
Bell EL, Klimova TA, Eisenbart J, Schumacker PT, Chandel NS. Mitochondrial reactive oxygen species trigger hypoxia-inducible factor-dependent extension of the replicative life span during hypoxia. Mol Cell Biol. 27: 5737-45, 2007.
Bilati U, Allémann E, Doelker ED. Development of a nanoprecipitation method intended for the entrapment of hydrophilic drugs into nanoparticles. Eur J Pharm Sci. 24: 67–75, 2005.
Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res. 63: 1270-9, 2003.
Boiadjieva S. Hallberg C, Högström M, Busch C. Methods in laboratory investigation. Exclusion of trypan blue from microcarriers by endothelial cells: an in vitro barrier function test. Lab Invest. 50: 239–246, 1984.
Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, McDonagh T, Lemieux M, McBurney M, Szilvasi A, Easlon EJ, Lin SJ, Guarente L. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol. 4:e31, 2006.
Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat. Rev. Cancer 9: 701-13, 2009.
Cartiera MA, Johnson KM, Rajendran V, et al. The uptake and intracellular fate of PLGA nanoparticles in epithelial cells. Biomaterials. 30: 2790-2798, 2009.
Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS and Jove R. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10: 105-15, 1999.
Chang CW, Wu SY, Chuang WJ, Lin YS, Wu JJ, Liu CC, Tsai PJ, Lin MT. The IL-8 production by Streptococcal pyrogenic exotoxin B. Exp. Biol. Med. (Maywood), 234: 1316-1326, 2009.
Chang CY, Chien SC, Chen TW, Lung CC, Chang JY. Chamaecypanone C, a novel skeleton microtubule inhibitor, with anticancer activity by trigger caspase 8-Fas/FasL dependent apoptotic pathway in human cancer cells. Biochem Pharmacol. 79: 1261-1271, 2010.
Cheng FY, Wang SP, Su CH, Tsai TL, Wu PC, Shieh DB, Chen JH, Hsieh PC, Yeh CS.; Stabilizer-free poly(lactide-co-glycolide) nanoparticles for multimodal biomedical probes. Biomaterials. 29: 2104-12, 2008.
Cheng FY, Su CH, Wu PC, Yeh CS. Multifunctional polymeric nanoparticles for combined chemotherapeutic and near-infrared photothermal cancer therapy in vitro and in vivo. Chem Commun (Camb). 46:3167-9, 2010.
Chu YW, Yang PC, Yang SC, Shyu YC, Hendrix MJ, Wu R, Wu CW. Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol. 17: 353-60, 1997.
Collins P, Jones C, Choudhury S, Damelin L, Hodgson H. Increased expression of uncoupling protein 2 in HepG2 cells attenuates oxidative damage and apoptosis. Liver Int 25: 880-887, 2005.
Collins TS, Lee LF, Ting JP. Paclitaxel up-regulates interleukin-8 synthesis in human lung carcinoma through an NF-kappaB- and AP-1-dependent mechanism. Cancer Immunol Immunother 49:78-84, 2000.
Cui W, Bei J, Wang S, Zhi G, Zhao Y, Zhou X, Zhang H, Xu Y. Preparation and evaluation of poly(L-lactide-co-glycolide) (PLGA) microbubbles as a contrast agent for myocardial contrast echocardiography. J Biomed Mater Res B Appl Biomater. 73: 171-8, 2005.
Darnell JE Jr. STATs and gene regulation. Science 277: 1630-5, 1997.
Davis ME, Chen ZG, Shin DM, Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov. 7: 771-782, 2008.
Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene 19: 2628-37, 2000.
Derdák Z, Fülöp P, Sabo E, Tavares R, Berthiaume EP, Resnick MB, Paragh G, Wands JR, Baffy G. Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress. Carcinogenesis 27: 956-961, 2006.
Derdák Z, Mark NM, Beldi G, Robson SC, Wands JR, Baffy G. The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells. Cancer Res 68: 2813-2819, 2008.
Devalapally H, Duan Z, Seiden MV, Amiji MM. Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles. Clin Cancer Res. 14: 3193-203, 2008.
Dong X, Mattingly CA, Tseng MT, Cho MJ, Liu Y, Adams VR, Mumper RJ. Doxorubicin and paclitaxel-loaded lipid-based nanoparticles overcome multidrug resistance by inhibiting P-glycoprotein and depleting ATP. Cancer Res. 69:3918-26, 2009.
Dong Y, Feng SS. In vitro and in vivo evaluation of methoxy polyethylene glycol-polylactide (MPEG-PLA) nanoparticles for small-molecule drug chemotherapy. Biomaterials. 28: 4154-4160,2007.
Duan Z, Bradner JE, Greenberg E, Levine R, Foster R, Mahoney J, Seiden MV. SD-1029 inhibits signal transducer and activator of transcription 3 nuclear translocation. Clin Cancer Res. 12: 6844-52, 2006.
Emre Y, Hurtaud C, Nübel T, Criscuolo F, Ricquier D, Cassard-Doulcier AM. Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages. Biochem J. 402: 271-8, 2007.
Fang J, Nakamura H, Iyer AK. Tumor-targeted induction of oxystress for cancer therapy. J Drug Target 15: 475-86, 2007.
Fruehauf JP, Meyskens Jr FL. Reactive oxygen species: a breath of life or death? Clin Cancer Res 13: 789-794, 2007.
Fuchs DA, Johnson RK. Cytologic evidence that taxol, an antineoplastic agent from Taxus brevifolia, acts as a mitotic spindle poison. Cancer Treat Rep 62: 1219-22, 1978.
Gaucher G, Marchessault RH, Leroux JC. Polyester-based micelles and nanoparticles for the parenteral delivery of taxanes. J Control Release. 143: 2-12, 2010.
Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, Yoder S, Enkemann S, Eschrich S, Lee JH, Beam CA, Cheng J, Minton S, Muro-Cacho CA, Jove R. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12: 11-9, 2006.
Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 21: 11-19, 2010.
Gwak SJ, Kim BS. Poly(lactic-co-glycolic acid) nanosphere as a vehicle for gene delivery to human cord blood-derived mesenchymal stem cells: comparison with polyethylenimine. Biotechnol Lett. 30: 1177-1182, 2008.
Heymach JV, Johnson BE, Prager D, Csada E, Roubec J, Pesek M, Spásová I, Belani CP, Bodrogi I, Gadgeel S, Kennedy SJ, Hou J, Herbst RS. Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. J Clin Oncol. 25: 4270-7, 2007.
Horimoto M, Resnick MB, Konkin TA, Routhier J, Wands JR, Baffy G. Expression of Uncoupling protein-2 in human colon cancer. Clin Cancer Res 10: 6203-6207, 2004.
Hsieh CC, Kuo YH, Kuo CC, Chen LT, Cheung CH, Chao TY, Lin CH, Pan WY,
Hu CM, Zhang L. Therapeutic Nanoparticles to Combat Cancer Drug Resistance. Curr Drug Metab. 10: 836-841, 2009.
Ikuta K, Takemura K, Kihara M, Nishimura M, Ueda N, Naito S, Lee E, Shimizu E, Yamauchi A. Overexpression of constitutive signal transducer and activator of transcription 3 mRNA in cisplatin-resistant human non-small cell lung cancer cells. Oncol Rep 13: 217-222, 2005
Jain RA. The manufacturing techniques of various drug loaded biodegradable poly(D,L-lactide-co-glyco-lide acid) (PLGA) devices. Biomaterials. 21: 2475–2490, 2000.
Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs. 16: 601-7, 2005.
Juntilla MM, Patil VD, Calamito M, Joshi RP, Birnbaum MJ, Koretzky GA. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood. 115: 4030-8, 2010.
Kawakami S, Hashida M. Targeted delivery systems of small interfering RNA by systemic administration. Drug Metab Pharmacokinet. 22: 142-51, 2007.
Kim HS, Oh JM, Jin DH, Yang KH, Moon EY. Paclitaxel induces vascular endothelial growth factor expression through reactive oxygen species production. Pharmacology, 81, 317-324, 2008.
Kim YH, Park JH, Lee M, Kim YH, Park TG, Kim SW. Polyethylenimine with acid-labile linkages as a biodegradable gene carrier. J Control Release. 103: 209-219, 2005.
Klimova T, Chandel NS. Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 15: 660-6, 2008.
Kubo M, Hanada T, Yoshimura A. Suppressors of cytokine signaling and immunity. Nat. Immunol. 4: 1169-1176, 2003.
Li Y. Trush MA. Diphenyleneiodonium, an NAD(P)H oxidase inhibitor, also potently inhibits mitochondrial reactive oxygen species production. Biochem. Biophys. Res. Commun. 253: 295-299, 1998.
Li ZY, Yang Y, Ming M, Liu B. Mitochondrial ROS generation for regulation of autophagic pathways in cancer. Biochem. Biophys. Res. Commun. 414: 5-8, 2011.
Ling X, Bernacki RJ, Brattain MG, Li F. Induction of survivin expression by taxol (paclitaxel) is an early event, which is independent of taxol-mediated G2/M arrest. J. Biol. Chem. 279: 15196-15203, 2004.
Liu B, Du L, Hong JS. Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther. 293: 607-17, 2000.
Liu H, Tekle C, Chen YW, Kristian A, Zhao Y, Zhou M, Liu Z, Ding Y, Wang B, Martindale JL, Holbrook NJ. Cellular response to oxidative stress: signaling for suicide and survival. J. Cell Physiol. 192: 1-15, 2002.
Liu T. Hannafon B, Gill L, Kelly W, Benbrook D. Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria. Mol. Cancer Ther. 6: 1814-1822, 2007.
Mailloux RJ, Adjeitey CN, Harper ME. Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents. PLoS One. 5: e13289, 2010.
Manfredi G, Yang L, Gajewski CD, Mattiazzi M. Measurements of ATP in mammalian cells. Methods 26: 317-326, 2002.
Martello LA, Verdier-Pinard P, Shen HJ, He L, Torres K, Orr GA, Horwitz SB. Elevated levels of microtubule destabilizing factors in a Taxol-resistant/ dependent A549 cell line with an alpha-tubulin mutation. Cancer Res. 63:1207-1213, 2003
Masuda A, Maeno K, Nakagawa T, Saito H, Takahashi T. Association between mitotic spindle checkpoint impairment and susceptibility to the induction of apoptosis by anti-microtubule agents in human lung cancers. Am. J. Pathol. 163: 1109-1116, 2003.
Mayur YC, Peters GJ, Prasad VV, Lemo C, Sathish NK. Design of new drug molecules to be used in reversing multidrug resistance in cancer cells. Curr Cancer Drug Targets. 9: 298-306, 2009.
Mælandsmo GM, Nesland JM, Fodstad O, Tan M. B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation. Mol. Cancer Ther 10: 960-971, 2011.
Meng H, Liong M, Xia T, Li Z, Ji Z, Zink JI, Nel AE. Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line. ACS Nano.4:4539-50, 2010.
Ng Dc, Lin BH, Lim CP, Huang G, Zhang T, Poli V, Cao X. Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin. J Cell Biol. 172: 245-257, 2006.
Ohkouchi S, Block GJ, Katsha AM, Kanehira M, Ebina M, Kikuchi T, Saijo Y, Nukiwa T, Prockop DJ. Mesenchymal Stromal Cells Protect Cancer Cells From ROS-induced Apoptosis and Enhance the Warburg Effect by Secreting STC1. Mol Ther 20: 417-23, 2012
Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev. 55:329-47, 2003.
Panyam J, Labhasetwar V. Sustained cytoplasmic delivery of drugs with intracellular receptors using biodegradable nanoparticles. Mol Pharm. 1:77-84, 2004.
Patil YB, Panyam J. Polymeric nanoparticles for siRNA delivery and gene silencing. Int J Pharm. 367: 195-203, 2009.
Patil YB, Swaminathan SK, Sadhukha T, Ma L, Panyam J. The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance. Biomaterials. 31: 358-365, 2010.
Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat 7: 97-110, 2004.
Peng XH, Karna P, Cao Z, Jiang BH, Zhou M, Yang L. Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1 alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem. 281: 25903-14, 2006.
Piñeiro D, Martín ME, Guerra N, Salinas M, González VM. Calpain inhibition stimulates caspase-dependent apoptosis induced by taxol in NIH3T3 cells. Exp Cell Res 313: 369-379, 2007.
Putral LN, Gu W, McMillan NA. RNA interference for the treatment of cancer. Drug News Perspect. 19: 317-24, 2006.
Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 15: 678-85, 2008.
Real PJ, Sierra A, De Juan A, Segovia JC, Lopez-Vega JM, Fernandez-Luna JL. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene 21: 7611-8, 2002.
Sahay G, Alakhova DY, Kabanov AV. Endocytosis of nanomedicines. J Control Release. 145: 182-195, 2010.
Samudio I, Fiegl M, McQueen T, Clise-Dwyer K, Andreeff M. The warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation. Cancer Res. 68: 5198-5205, 2008.
Sastre-Serra J, Valle A, Company MM, Garau I, Oliver J, Roca P. Estrogen down-regulates uncoupling proteins and increases oxidative stress in breast cancer. Free Radic Biol Med 48: 506-12, 2010.
Sayeed A, Meng Z, Luciani G, Chen LC, Bennington JL, Dairkee SH. Negative regulation of UCP2 by TGFβ signaling characterizes low and intermediate-grade primary breast Cancer. Cell Death Dis 1: e53, 2010.
Scagliotti GV. Potential role of multi-targeted tyrosine kinase inhibitors in non-small-cell lung cancer. Ann Oncol. Suppl 10: x32-41, 2007.
Schiff PB, Horwitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci U S A 77: 1561-5, 1980.
Selimovic D, Hassan M, Haikel Y, Hengge UR. Taxol-induced mitochondrial stress in melanoma cells is mediated by activation of c-Jun N-terminal kinase (JNK) and p38 pathways via uncoupling protein 2. Cell Signal 20: 311-322, 2008.
Semenkovich CF. PPARalpha suppresses insulin secretion and induces UCP2 in insulinoma cells. J Lipid Res. 43: 936-43, 2002.
Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 9: 563-75, 2009.
Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol Cell Physiol 275: C1640-C1652, 1998.
Song L, Turkson J, Karras JG, Jove R and Haura EB. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 22: 4150-65, 2003.
Soussi T. p53 mutations and resistance to chemotherapy: A stab in the back for p73. Cancer Cell 3: 303-305, 2003.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl. Cancer Inst. 92: 205-216, 2000.
Tordjman K, Standley KN, Bernal-Mizrachi C, Leone TC, Coleman T, Kelly DP, Tu Y, Renner S, Xu F, Fleishman A, Taylor J, Weisz J, Vescio R, Rettig M, Berenson J, Krajewski S, Reed JC and Lichtenstein A. BCL-XL expression in multiple myeloma: possible indicator of chemoresistance. Cancer Res 58: 256-62, 1998.
Varbiro G, Veres B, Gallyas Jr F, Sumegi B. Direct effect of Taxol on free radical formation and mitochondrial permeability transition. Free Radic Biol Med 31: 548-58, 2001.
Walker SR. Chaudhury M, Nelson EA, Frank DA. Microtubule-targeted chemotherapeutic agents inhibit signal transducer and activator of transcription 3 (STAT3) signaling. Mol. Pharmacol. 78: 903-908, 2010.
Wang F, Fu X, Chen X, Chen X, Zhao Y. Mitochondrial uncoupling inhibits p53 mitochondrial translocation in TPA-challenged skin epidermal JB6 cells. PLoS One. 5: e13459, 2010.
Wang J. Yi J. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol. Ther 7: 1875-1884, 2008.
Wang Y, Gao S, Ye WH, Yoon HS, Yang YY. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer. Nat Mater. 5: 791-6, 2006.
Wang YF, Chen CY, Chung SF, Chiou YH, Lo HR. Involvement of oxidative stress and caspase activation in paclitaxel-induced apoptosis of primary effusion lymphoma cells. Cancer Chemother. Pharmacol, 54: 322-330, 2004.
Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, Moh A, Moghaddas S, Chen Q, Bobbili S, Cichy J, Dulak J, Baker DP, Wolfman A, Stuehr D, Hassan MO, Fu XY, Avadhani N, Drake JI, Fawcett P, Lesnefsky EJ, Larner AC. Function of mitochondrial Stat3 in cellular respiration. Science 323: 793-797, 2009.
Winograd-Katz SE, Levitzki A. Cisplatin induces PKB/Akt activation and p38(MAPK) phosphorylation of the EGF receptor. Oncogene 25: 7381-90, 2006.
Xia T, Kovochich M, Liong M, Zink JI, Nel AE. Cationic polystyrene nanosphere toxicity depends on cell-specific endocytic and mitochondrial injury pathways. ACS Nano. 2:85-96, 2008.
Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S, Gritsko T, Turkson J, Kay H, Semenza GL, Cheng JQ, Jove R, Yu H. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene. 24: 5552-60, 2005.
Yeh HH, Lai WW, Chen HH, Liu HS and Su WC.: Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion. Oncogene. 25: 4300-9, 2006.
Yezhelyev MV, Qi L, O’Regan RM, Nie S, Gao X.: Proton-Sponge Coated Quantum Dots for siRNA Delivery and Intracellular Imaging. J. Am. Chem. Soc., 130:9006–12, 2008.
You L. Yang CT, Jablons DM. ONYX-015 works synergistically with chemotherapy in lung cancer cell lines and primary cultures freshly made from lung cancer patients. Cancer Res 60: 1009-1113, 2000.
Yuan X, Naguib S, Wu Z. Recent advances of siRNA delivery by nanoparticles. Expert Opin Drug Deliv. 8: 521-536, 2011.
Zeng L, Kizaka-Kondoh S, Itasaka S, Xie X, Inoue M, Tanimoto K, Shibuya K, Hiraoka M. Hypoxia inducible factor-1 influences sensitivity to paclitaxel of human lung cancer cell lines under normoxic conditions. Cancer Sci. 98: 1394-401, 2007.
Zhang X, Li Y, Chen X, Wang X, Xu X, Liang Q, Hu J, Jing X. Synthesis and characterization of the paclitaxel/MPEG-PLA block copolymer conjugate. Biomaterials. 26: 2121-2128, 2005.