The pharmacological bases of the antiangiogenic activity of paclitaxel

Guido Bocci, Antonello Di Paolo, Romano Danesi, Guido Bocci, Antonello Di Paolo, Romano Danesi

Abstract

In the mid 1990s, researchers began to investigate the antiangiogenic activity of paclitaxel as a possible additional mechanism contributing to its antineoplastic activity in vivo. In the last decade, a number of studies showed that paclitaxel has antiangiogenic activity that could be ascribed to the inhibition of either tubule formation or cell migration, and to an antiproliferative effect towards activated endothelial cells. Furthermore, paclitaxel was shown to downregulate VEGF and Ang-1 expression in tumor cells, and to increase the secretion of TSP-1 in the tumor microenvironment. Moreover, the new pharmaceutical formulations of paclitaxel (such as liposome-encapsulated paclitaxel, ABI-007, and paclitaxel entrapped in emulsifying wax nanoparticles) enhanced the in vivo antiangiogenic activity of the drug. Thus, the preclinical data of paclitaxel may be exploited to implement a novel and rational therapeutic strategy to control tumor progression in patients.

Figures

Fig. 1
Fig. 1
Antiangiogenic activity of paclitaxel. EPC endothelial progenitor cells, TSP-1 thrombospondin-1, Ang-1 angiopoetin-1, VEGF vascular endothelial growth factor
Fig. 2
Fig. 2
Molecular and cellular mechanisms of antiangiogenic activity of paclitaxel

References

    1. Singh S, Dash AK. Paclitaxel in cancer treatment: perspectives and prospects of its delivery challenges. Crit Rev Ther Drug Carrier Syst. 2009;26(4):333–372. doi: 10.1615/CritRevTherDrugCarrierSyst.v26.i4.10.
    1. Schwartz EL. Antivascular actions of microtubule-binding drugs. Clin Cancer Res. 2009;15(8):2594–2601. doi: 10.1158/1078-0432.CCR-08-2710.
    1. Pasquier E, Andre N, Braguer D. Targeting microtubules to inhibit angiogenesis and disrupt tumour vasculature: implications for cancer treatment. Curr Cancer Drug Targets. 2007;7(6):566–581. doi: 10.2174/156800907781662266.
    1. Pasquier E, Honore S, Braguer D. Microtubule-targeting agents in angiogenesis: where do we stand? Drug Resist Updat. 2006;9(1–2):74–86. doi: 10.1016/j.drup.2006.04.003.
    1. Dordunoo SK, Jackson JK, Arsenault LA, Oktaba AM, Hunter WL, Burt HM. Taxol encapsulation in poly(epsilon-caprolactone) microspheres. Cancer Chemother Pharmacol. 1995;36(4):279–282. doi: 10.1007/BF00689043.
    1. Belotti D, Vergani V, Drudis T, Borsotti P, Pitelli MR, Viale G, Giavazzi R, Taraboletti G. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res. 1996;2(11):1843–1849.
    1. Klauber N, Parangi S, Flynn E, Hamel E, D’Amato RJ. Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res. 1997;57(1):81–86.
    1. Iwahana M, Utoguchi N, Mayumi T, Goryo M, Okada K. Drug resistance and P-glycoprotein expression in endothelial cells of newly formed capillaries induced by tumors. Anticancer Res. 1998;18(4C):2977–2980.
    1. Lau DH, Xue L, Young LJ, Burke PA, Cheung AT. Paclitaxel (Taxol): an inhibitor of angiogenesis in a highly vascularized transgenic breast cancer. Cancer Biother Radiopharm. 1999;14(1):31–36. doi: 10.1089/cbr.1999.14.31.
    1. Lissoni P, Fugamalli E, Malugani F, Ardizzoia A, Secondino S, Tancini G, Gardani GS. Chemotherapy and angiogenesis in advanced cancer: vascular endothelial growth factor (VEGF) decline as predictor of disease control during taxol therapy in metastatic breast cancer. Int J Biol Markers. 2000;15(4):308–311.
    1. Guo L, Burke P, Lo SH, Gandour-Edwards R, Lau D. Quantitative analysis of angiogenesis using confocal laser scanning microscopy. Angiogenesis. 2001;4(3):187–191. doi: 10.1023/A:1014010801754.
    1. Myoung H, Hong SD, Kim YY, Hong SP, Kim MJ. Evaluation of the anti-tumor and anti-angiogenic effect of paclitaxel and thalidomide on the xenotransplanted oral squamous cell carcinoma. Cancer Lett. 2001;163(2):191–200. doi: 10.1016/S0304-3835(00)00701-1.
    1. Fox WD, Higgins B, Maiese KM, Drobnjak M, Cordon-Cardo C, Scher HI, Agus DB. Antibody to vascular endothelial growth factor slows growth of an androgen-independent xenograft model of prostate cancer. Clin Cancer Res. 2002;8(10):3226–3231.
    1. Ryschich E, Werner J, Gebhard MM, Klar E, Schmidt J. Angiogenesis inhibition with TNP-470, 2-methoxyestradiol, and paclitaxel in experimental pancreatic carcinoma. Pancreas. 2003;26(2):166–172. doi: 10.1097/00006676-200303000-00013.
    1. Kerbel RS, Viloria-Petit A, Klement G, Rak J. ‘Accidental’ anti-angiogenic drugs. Anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples. Eur J Cancer. 2000;36(10):1248–1257. doi: 10.1016/S0959-8049(00)00092-7.
    1. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4(6):423–436. doi: 10.1038/nrc1369.
    1. Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 2000;105(8):R15–R24. doi: 10.1172/JCI8829.
    1. Bocci G, Nicolaou KC, Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res. 2002;62(23):6938–6943.
    1. Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, Folkman J. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60(7):1878–1886.
    1. Hayot C, Farinelle S, De Decker R, Decaestecker C, Darro F, Kiss R, Van Damme M. In vitro pharmacological characterizations of the anti-angiogenic and anti-tumor cell migration properties mediated by microtubule-affecting drugs, with special emphasis on the organization of the actin cytoskeleton. Int J Oncol. 2002;21(2):417–425.
    1. Hotchkiss KA, Ashton AW, Mahmood R, Russell RG, Sparano JA, Schwartz EL. Inhibition of endothelial cell function in vitro and angiogenesis in vivo by docetaxel (Taxotere): association with impaired repositioning of the microtubule organizing center. Mol Cancer Ther. 2002;1(13):1191–1200.
    1. Dicker AP, Williams TL, Iliakis G, Grant DS. Targeting angiogenic processes by combination low-dose paclitaxel and radiation therapy. Am J Clin Oncol. 2003;26(3):e45–e53.
    1. Grant DS, Williams TL, Zahaczewsky M, Dicker AP. Comparison of antiangiogenic activities using paclitaxel (taxol) and docetaxel (taxotere) Int J Cancer. 2003;104(1):121–129. doi: 10.1002/ijc.10907.
    1. Wang J, Lou P, Lesniewski R, Henkin J. Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly. Anticancer Drugs. 2003;14(1):13–19. doi: 10.1097/00001813-200301000-00003.
    1. Wang F, Cao Y, Liu HY, Xu SF, Han R. Anti-invasion and anti-angiogenesis effect of taxol and camptothecin on melanoma cells. J Asian Nat Prod Res. 2003;5(2):121–129. doi: 10.1080/1028602021000054973.
    1. Vacca A, Ribatti D, Iurlaro M, Merchionne F, Nico B, Ria R, Dammacco F. Docetaxel versus paclitaxel for antiangiogenesis. J Hematother Stem Cell Res. 2002;11(1):103–118. doi: 10.1089/152581602753448577.
    1. Albertsson P, Lennernas B, Norrby K. Chemotherapy and antiangiogenesis: drug-specific effects on microvessel sprouting. APMIS. 2003;111(11):995–1003.
    1. Lennernas B, Albertsson P, Damber JE, Norrby K. Antiangiogenic effect of metronomic paclitaxel treatment in prostate cancer and non-tumor tissue in the same animals: a quantitative study. APMIS. 2004;112(3):201–209. doi: 10.1111/j.1600-0463.2004.apm1120306.x.
    1. Zhang M, Tao W, Pan S, Sun X, Jiang H. Low-dose metronomic chemotherapy of paclitaxel synergizes with cetuximab to suppress human colon cancer xenografts. Anticancer Drugs. 2009;20(5):355–363. doi: 10.1097/CAD.0b013e3283299f36.
    1. Jiang H, Tao W, Zhang M, Pan S, Kanwar JR, Sun X. Low-dose metronomic paclitaxel chemotherapy suppresses breast tumors and metastases in mice. Cancer Invest. 2010;28(1):74–84. doi: 10.3109/07357900902744510.
    1. Wang F, Cao Y, Zhao W, Liu H, Fu Z, Han R. Taxol inhibits melanoma metastases through apoptosis induction, angiogenesis inhibition, and restoration of E-cadherin and nm23 expression. J Pharmacol Sci. 2003;93(2):197–203. doi: 10.1254/jphs.93.197.
    1. Lau D, Guo L, Gandara D, Young LJ, Xue L. Is inhibition of cancer angiogenesis and growth by paclitaxel schedule dependent? Anticancer Drugs. 2004;15(9):871–875. doi: 10.1097/00001813-200410000-00007.
    1. Lyons JM, 3rd, Anthony CT, Thomson JL, Woltering EA. A novel assay to assess the effectiveness of antiangiogenic drugs in human breast cancer. Ann Surg Oncol. 2008;15(12):3407–3414. doi: 10.1245/s10434-008-0145-2.
    1. Muta M, Yanagawa T, Sai Y, Saji S, Suzuki E, Aruga T, Kuroi K, Matsumoto G, Toi M, Nakashima E. Effect of low-dose paclitaxel and docetaxel on endothelial progenitor cells. Oncology. 2009;77(3–4):182–191. doi: 10.1159/000236016.
    1. Merchan JR, Jayaram DR, Supko JG, He X, Bubley GJ, Sukhatme VP. Increased endothelial uptake of paclitaxel as a potential mechanism for its antiangiogenic effects: potentiation by Cox-2 inhibition. Int J Cancer. 2005;113(3):490–498. doi: 10.1002/ijc.20595.
    1. Fitzpatrick FA, Wheeler R. The immunopharmacology of paclitaxel (taxol), docetaxel (taxotere), and related agents. Int Immunopharmacol. 2003;3(13–14):1699–1714. doi: 10.1016/j.intimp.2003.08.007.
    1. Olsen SR. Taxanes and COX-2 inhibitors: from molecular pathways to clinical practice. Biomed Pharmacother. 2005;59(Suppl 2):S306–S310. doi: 10.1016/S0753-3322(05)80052-6.
    1. Napoleone E, Zurlo F, Latella MC, Amore C, Di Santo A, Iacoviello L, Donati MB, Lorenzet R. Paclitaxel downregulates tissue factor in cancer and host tumour-associated cells. Eur J Cancer. 2009;45(3):470–477. doi: 10.1016/j.ejca.2008.10.014.
    1. Chen CA, Ho CM, Chang MC, Sun WZ, Chen YL, Chiang YC, Syu MH, Hsieh CY, Cheng WF. Metronomic chemotherapy enhances antitumor effects of cancer vaccine by depleting regulatory T lymphocytes and inhibiting tumor angiogenesis. Mol Ther. 2010;18(6):1233–1243. doi: 10.1038/mt.2010.34.
    1. Pasquier E, Carre M, Pourroy B, Camoin L, Rebai O, Briand C, Braguer D. Antiangiogenic activity of paclitaxel is associated with its cytostatic effect, mediated by the initiation but not completion of a mitochondrial apoptotic signaling pathway. Mol Cancer Ther. 2004;3(10):1301–1310.
    1. Pasquier E, Honore S, Pourroy B, Jordan MA, Lehmann M, Briand C, Braguer D. Antiangiogenic concentrations of paclitaxel induce an increase in microtubule dynamics in endothelial cells but not in cancer cells. Cancer Res. 2005;65(6):2433–2440. doi: 10.1158/0008-5472.CAN-04-2624.
    1. Murtagh J, Lu H, Schwartz EL. Taxotere-induced inhibition of human endothelial cell migration is a result of heat shock protein 90 degradation. Cancer Res. 2006;66(16):8192–8199. doi: 10.1158/0008-5472.CAN-06-0748.
    1. Bijman MN, van Nieuw Amerongen GP, Laurens N, van Hinsbergh VW, Boven E. Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton. Mol Cancer Ther. 2006;5(9):2348–2357. doi: 10.1158/1535-7163.MCT-06-0242.
    1. Bonezzi K, Belotti D, North BJ, Ghilardi C, Borsotti P, Resovi A, Ubezio P, Riva A, Giavazzi R, Verdin E, Taraboletti G. Inhibition of SIRT2 potentiates the anti-motility activity of taxanes: implications for antineoplastic combination therapies. Neoplasia. 2012;14(9):846–854.
    1. Bocci G, Francia G, Man S, Lawler J, Kerbel RS. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA. 2003;100(22):12917–12922. doi: 10.1073/pnas.2135406100.
    1. Damber JE, Vallbo C, Albertsson P, Lennernas B, Norrby K. The anti-tumour effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin. Cancer Chemother Pharmacol. 2006;58(3):354–360. doi: 10.1007/s00280-005-0163-8.
    1. Hata K, Osaki M, Dhar DK, Nakayama K, Fujiwaki R, Ito H, Nagasue N, Miyazaki K. Evaluation of the antiangiogenic effect of taxol in a human epithelial ovarian carcinoma cell line. Cancer Chemother Pharmacol. 2004;53(1):68–74.
    1. Loo WT, Fong JH, Cheung MN, Chow LW. The efficacy of paclitaxel on solid tumour analysed by ATP bioluminescence assay and VEGF expression: a translational research study. Biomed Pharmacother. 2005;59(Suppl 2):S337–S339. doi: 10.1016/S0753-3322(05)80069-1.
    1. Thijssen VL, Brandwijk RJ, Dings RP, Griffioen AW. Angiogenesis gene expression profiling in xenograft models to study cellular interactions. Exp Cell Res. 2004;299(2):286–293. doi: 10.1016/j.yexcr.2004.06.014.
    1. Byrne JD, Betancourt T, Brannon-Peppas L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev. 2008;60(15):1615–1626. doi: 10.1016/j.addr.2008.08.005.
    1. Straubinger RM, Arnold RD, Zhou R, Mazurchuk R, Slack JE. Antivascular and antitumor activities of liposome-associated drugs. Anticancer Res. 2004;24(2A):397–404.
    1. Sharma A, Sharma US, Straubinger RM. Paclitaxel-liposomes for intracavitary therapy of intraperitoneal P388 leukemia. Cancer Lett. 1996;107(2):265–272. doi: 10.1016/0304-3835(96)04380-7.
    1. Poste G, Bucana C, Raz A, Bugelski P, Kirsh R, Fidler IJ. Analysis of the fate of systemically administered liposomes and implications for their use in drug delivery. Cancer Res. 1982;42(4):1412–1422.
    1. Thurston G, McLean JW, Rizen M, Baluk P, Haskell A, Murphy TJ, Hanahan D, McDonald DM. Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice. J Clin Invest. 1998;101(7):1401–1413. doi: 10.1172/JCI965.
    1. Schmitt-Sody M, Strieth S, Krasnici S, Sauer B, Schulze B, Teifel M, Michaelis U, Naujoks K, Dellian M. Neovascular targeting therapy: paclitaxel encapsulated in cationic liposomes improves antitumoral efficacy. Clin Cancer Res. 2003;9(6):2335–2341.
    1. Kunstfeld R, Wickenhauser G, Michaelis U, Teifel M, Umek W, Naujoks K, Wolff K, Petzelbauer P. Paclitaxel encapsulated in cationic liposomes diminishes tumor angiogenesis and melanoma growth in a “humanized” SCID mouse model. J Invest Dermatol. 2003;120(3):476–482. doi: 10.1046/j.1523-1747.2003.12057.x.
    1. Bode C, Trojan L, Weiss C, Kraenzlin B, Michaelis U, Teifel M, Alken P, Michel MS. Paclitaxel encapsulated in cationic liposomes: a new option for neovascular targeting for the treatment of prostate cancer. Oncol Rep. 2009;22(2):321–326.
    1. Moghimi SM, Patel HM. Opsonophagocytosis of liposomes by peritoneal macrophages and bone marrow reticuloendothelial cells. Biochim Biophys Acta. 1992;1135(3):269–274. doi: 10.1016/0167-4889(92)90230-9.
    1. Huang Y, Chen XM, Zhao BX, Ke XY, Zhao BJ, Zhao X, Wang Y, Zhang X, Zhang Q. Antiangiogenic activity of sterically stabilized liposomes containing paclitaxel (SSL-PTX): in vitro and in vivo. AAPS PharmSciTech. 2010;11(2):752–759. doi: 10.1208/s12249-010-9430-z.
    1. Koziara JM, Whisman TR, Tseng MT, Mumper RJ. In-vivo efficacy of novel paclitaxel nanoparticles in paclitaxel-resistant human colorectal tumors. J Control Release. 2006;112(3):312–319. doi: 10.1016/j.jconrel.2006.03.001.
    1. Hammady T, Rabanel JM, Dhanikula RS, Leclair G, Hildgen P. Functionalized nanospheres loaded with anti-angiogenic drugs: cellular uptake and angiosuppressive efficacy. Eur J Pharm Biopharm. 2009;72(2):418–427. doi: 10.1016/j.ejpb.2009.01.007.
    1. Fu Q, Sun J, Zhang W, Sui X, Yan Z, He Z. Nanoparticle albumin-bound (NAB) technology is a promising method for anti-cancer drug delivery. Recent Pat Anticancer Drug Discov. 2009;4(3):262–272. doi: 10.2174/157489209789206869.
    1. Miele E, Spinelli GP, Tomao F, Tomao S. Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer. Int J Nanomedicine. 2009;4:99–105.
    1. Yamamoto Y, Kawano I, Iwase H. Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval. Onco Targets Ther. 2011;4:123–136. doi: 10.2147/OTT.S13836.
    1. Ng SS, Sparreboom A, Shaked Y, Lee C, Man S, Desai N, Soon-Shiong P, Figg WD, Kerbel RS. Influence of formulation vehicle on metronomic taxane chemotherapy: albumin-bound versus cremophor EL-based paclitaxel. Clin Cancer Res. 2006;12(14 Pt 1):4331–4338. doi: 10.1158/1078-0432.CCR-05-2762.
    1. Ng SS, Figg WD, Sparreboom A. Taxane-mediated antiangiogenesis in vitro: influence of formulation vehicles and binding proteins. Cancer Res. 2004;64(3):821–824. doi: 10.1158/0008-5472.CAN-03-3391.
    1. Lee SJ, Ghosh SC, Han HD, Stone RL, Bottsford-Miller J, Shen DY, Auzenne E, Lopez-Araujo A, Lu C, Nishimura M, Pecot CV, Zand B, Thanapprapa D, Sr, Jennings NB, Kang Y, Huang J, Hu W, Klostergaard J, Sood AK. Metronomic activity of CD44-targeted hyaluronic acid-paclitaxel in ovarian carcinoma. Clin Cancer Res. 2012;18:4114–4121. doi: 10.1158/1078-0432.CCR-11-3250.
    1. Liang L, Lin SW, Dai W, Lu JK, Yang TY, Xiang Y, Zhang Y, Li RT, Zhang Q. Novel cathepsin B-sensitive paclitaxel conjugate: higher water solubility, better efficacy and lower toxicity. J Control Release. 2012;160(3):618–629. doi: 10.1016/j.jconrel.2012.02.020.
    1. Moes J, Koolen S, Huitema A, Schellens J, Beijnen J, Nuijen B. Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel. Eur J Pharm Biopharm. 2012
    1. Kerbel RS. Strategies for improving the clinical benefit of antiangiogenic drug based therapies for breast cancer. J Mammary Gland Biol Neoplasia. 2012
    1. Rodrigues G, Sanatani M. Age and comorbidity considerations related to radiotherapy and chemotherapy administration. Semin Radiat Oncol. 2012;22(4):277–283. doi: 10.1016/j.semradonc.2012.05.004.
    1. Emmenegger U, Francia G, Chow A, Shaked Y, Kouri A, Man S, Kerbel RS. Tumors that acquire resistance to low-dose metronomic cyclophosphamide retain sensitivity to maximum tolerated dose cyclophosphamide. Neoplasia. 2011;13(1):40–48.
    1. Allegrini G, Di Desidero T, Barletta MT, Fioravanti A, Orlandi P, Canu B, Chericoni S, Loupakis F, Di Paolo A, Masi G, Fontana A, Lucchesi S, Arrighi G, Giusiani M, Ciarlo A, Brandi G, Danesi R, Kerbel RS, Falcone A, Bocci G. Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers. Angiogenesis. 2012;15(2):275–286. doi: 10.1007/s10456-012-9260-6.
    1. Allegrini G, Falcone A, Fioravanti A, Barletta MT, Orlandi P, Loupakis F, Cerri E, Masi G, Di Paolo A, Kerbel RS, Danesi R, Del Tacca M, Bocci G. A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients. Br J Cancer. 2008;98(8):1312–1319. doi: 10.1038/sj.bjc.6604311.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit