BACKGROUND: In this study, the effect of novel taxane SB-T-1216 and paclitaxel on sensitive MDA-MB-435 and resistant NCI/ADR-RES human breast cancer cells was compared. MATERIALS AND METHODS: Cell growth and survival were evaluated after 96-hour incubation with tested concentrations of taxanes. The effect on the formation of microtubule bundles was assessed employing fluorescence microscopy and on the cell cycle employing flow cytometric analysis. The activity of caspases was assessed employing commercial colorimetric kits. RESULTS: The IC(50) (concentration resulting in 50% of living cells in comparison with the control) of SB-T-1216 in sensitive cells was 0.6 nM versus 1 nM for paclitaxel. However, the IC(50) of SB-T-1216 in resistant cells was 1.8 nM versus 300 nM for paclitaxel. Both SB-T-1216 and paclitaxel at death-inducing concentrations induced the formation of microtubule bundles in sensitive as well as resistant cells. Cell death induced in sensitive and resistant cells by paclitaxel was associated with the accumulation of cells in the G(2)/M phase. On the contrary, cell death induced by SB-T-1216 took place without the accumulation of cells in the G(2)/M phase but with a decreased number of G(1) cells and the accumulation of hypodiploid cells. Both SB-T-1216 and paclitaxel activated caspase-3, caspase-9, caspase-2 and caspase-8 in sensitive as well as resistant cells. CONCLUSION: Cell death induced by both paclitaxel and novel taxane SB-T-1216 in breast cancer cells is associated with caspase activation and with the formation of interphase microtubule bundles. Novel taxane SB-T-1216, but not paclitaxel, seems to be capable of inducing cell death without the accumulation of cells in the G(2)/M phase.

Department of Cell and Molecular Biology 3rd Faculty of Medicine Charles University Ruská 87 10000 Prague 10 Czech Republic

Zobrazit více v PubMed

Rowinsky EK. The development and clinical utility of taxane class of antimicrotubule chemotherapy agents. Annu Rev Med. 1997;48:353–374. PubMed

Vaishampayan U, Parchment RE, Jasti BR, Hussain M. Taxanes: an overview of the pharmacokinetics and pharmacodynamics. Urology. 1999;54:22–29. PubMed

Choy H. Taxanes in combined modality therapy for solid tumors. Crit Rev Oncol Hematol. 2001;37:237–247. PubMed

Miller ML, Ojima I. Chemistry and chemical biology of taxane anticancer agents. Chem Record. 2001;1:195–211. PubMed

Ganansia-Leymarie V, Bischoff P, Bergerat JP, Holl V. Signal transduction pathways of taxane-induced apoptosis. Curr Med Chem Anticancer Agents. 2003;3:291–306. PubMed

Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB. Mechanisms of taxol resistance related to microtubules. Oncogene. 2003;22:7280–7295. PubMed PMC

Tuszynski JA, Trpišová B, Sept D, Brown JA. Selected physical issues in the structure and function of microtubules. J Struct Biol. 1997;118:94–106. PubMed

Brinkley BR. Managing the centrosome numbers game: from chaos to stability in cancer cell division. Trends Cell Biol. 2001;11:18–21. PubMed

Spencer MC, Faulds D. Paclitaxel: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of cancer. Drugs. 1994;48:795–845. PubMed

Xiao H, Verdier-Pinard P, Fernandez-Fuentes N, Burd B, Angeletti R, Fiser A, Horwitz SB, Orr GA. Insights into the mechanism of microtubule stabilization by Taxol. Proc Natl Acad Sci USA. 2006;103:10166–10173. PubMed PMC

Larroque AL, Dubois J, Thoret S, Aubert G, Chiaroni A, Guéritte F, Guénard D. Novel C2-3′ N-peptide-linked macrocyclic taxoids. Part 2: synthesis and biological activities of docetaxel analogues with a peptide side chain at C2 and their macrocyclic derivatives. Bioorg Med Chem. 2007;15:563–574. PubMed

Sackett D, Fojo T. Taxanes. Cancer Chemother Biol Response Modif. 1997;17:59–79. PubMed

Jordan MA, Ojima I, Rosas F, Distefano M, Wilson L, Scambia G, Ferlini C. Effects of novel taxanes SB-T-1213 and IDN5109 on tubulin polymerization and mitosis. Chem Biol. 2002;9:93–101. PubMed

Fan W. Possible mechanisms of paclitaxel-induced apoptosis. Biochem Pharmacol. 1999;57:1215–1221. PubMed

Aoudjit F, Vuori K. Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells. Oncogene. 2001;20:4995–5004. PubMed

Ehrlichová M, Koc M, Truksa J, Nad’ová Z, Václavíková R, Kovář J. Cell death induced by taxanes in breast cancer cells: cytochrome c is released in resistant but not in sensitive cells. Anticancer Res. 2005;25:4215–4224. PubMed

Nicoletti MI, Colombo T, Rossi C, Monardo C, Stura S, Zucchetti M, Riva A, Morazzoni P, Donati MB, Bombardelli E, D’Incalci M, Giavazzi R. IDN5109, a taxane with oral bioavailability and potent antitumor activity. Cancer Res. 2000;60:842–846. PubMed

Ehrlichová M, Václavíková R, Ojima I, Pepe A, Kuznetsova LV, Chen J, Truksa J, Kovář J, Gut I. Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells. N-S Arch Pharmacol. 2005;372:95–105. PubMed

Ferlini C, Raspaglio G, Mozzetti S, Cicchillitti L, Filippetti F, Gallo D, Fattorusso C, Campiani G, Scambia G. The seco-taxane IDN5390 is able to target class III beta-tubulin and to overcome paclitaxel resistance. Cancer Res. 2005;65:2397–2405. PubMed

Geney R, Chen J, Ojima I. Recent advances in the new generation taxane anticancer agents. Med Chem. 2005;1:125–139. PubMed

Ojima I, Chen J, Sun L, Borella CP, Wang T, Miller ML, Lin S, Geng X, Kuznetsova L, Qu C, Gallager D, Zhao X, Zanardi I, Xia S, Horwitz SB, Mallen-St Clair J, Guerriero JL, Bar-Sagi D, Veith JM, Pera P, Bernacki RJ. Design, Synthesis and biological evaluation of new generation taxoids. J Med Chem. 2008;51:3203–3221. PubMed PMC

Rowinsky EK, Calvo E. Novel agents that target tubulin and related elements. Semin Oncol. 2006;33:421–435. PubMed

Musílková J, Kovář J. Additive stimulatory effect of extracellular calcium and potassium on non-transferrin ferric iron uptake by HeLa and K562 cells. Biochim Biophys Acta. 2001;1514:117–126. PubMed

Kovář J, Valenta T, Štýbrová H. Differing sensitivity of tumor cells to apoptosis induced by iron deprivation in vitro. In Vitro Cell Dev Biol Anim. 2001;37:450–458. PubMed

Koc M, Nad’ová Z, Truksa J, Ehrlichová M, Kovář J. Iron deprivation induces apoptosis via mitochondrial changes related to Bax translocation. Apoptosis. 2005;10:381–393. PubMed

Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985;150:76–85. PubMed

Chen JG, Yang CP, Cammer M, Horwitz SB. Gene expression and mitotic exit induced by microtubule-stabilizing drugs. Cancer Res. 2003;63:7891–7899. PubMed

Ikui AE, Yang CH, Matsumoto T, Horwitz SB. Low concentrations of taxol cause mitotic delay followed by premature dissociation of p55CDC from Mad2 and BubR1 and abrogation of the spindle checkpoint, leading to aneuploidy. Cell Cycle. 2005;4:1385–1388. PubMed

Estève MA, Carré M, Braguer D. Microtubules in apoptosis induction: are they necessary? Curr Cancer Drug Targets. 2007;7:325–334. PubMed

Torres K, Horwitz SB. Mechanisms of taxol induced cell death are concentration dependent. Cancer Res. 1998;58:3620–3626. PubMed

Kottke TJ, Blajeski AL, Martins LM, Mesner PW, Jr, Davidson NE, Earnshaw WC, Armstrong DK, Kaufmann SH. Comparison of paclitaxel-, 5-fluoro-2′-deoxyuridine-, and epidermal growth factor (EGF)- induced apoptosis. Evidence for EGF-induced anokis. J Biol Chem. 1999;274:15927–15936. PubMed

Friedrich K, Wieder T, Von Haefen C, Radetzki S, Janicke R, Schulze-Osthoff K, Dorken B, Daniel PT. Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance. Oncogene. 2001;20:2749–2760. PubMed

André N, Carré M, Brasseur G, Pourroy B, Kovacic H, Briand C, Braguer D. Paclitaxel targets mitochondria upstream of caspase activation in intact human neuroblastoma cells. FEBS Lett. 2002;532:256–260. PubMed

Kolfschoten G, Hulscher TM, Duyndam MCA, Pinedo HM, Boven E. Variation in the kinetics of caspase-3 activation, Bcl-2 phosphorylation and apoptotic morphology in unselected human ovarian cancer cell lines as a response to docetaxel. Biochem Pharmacol. 2002;63:733–743. PubMed

Jiang S, Zu Y, Fu Y, Zhang Y, Efferth T. Activation of the mitochondria-driven pathway of apoptosis in human PC-3 prostate cancer cells by a novel hydrophilic paclitaxel derivative, 7-xylosyl-10-deacetylpaclitaxel. Int J Oncol. 2008;33:103–111. PubMed

Zhivotovsky B, Orrenius S. Caspase-2 function in response to DNA damage. Biochem Biophys Res Commun. 2005;331:859–867. PubMed

Ho LH, Read SH, Dorstyn L, Lambrusco L, Kumar S. Caspase-2 is required for cell death induced by cytoskeletal disruption. Oncogene. 2008;27:3393–3404. PubMed

Yuan SY, Hsu SL, Tsai KJ, Yang CR. Involvement of mitochondrial pathway in taxol-induced apoptosis of human T24 bladder cancer cells. Urol Res. 2002;30:282–288. PubMed

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. 2004;54:322–330. PubMed

Mhaidat NM, Wang Y, Kiejda KA, Zhang XD, Hersey P. Docetaxel-induced apoptosis in melanoma cells is dependent on activation of caspase-2. Mol Cancer Ther. 2007;6:752–761. PubMed

Chen H, Chung S, Sukumar S. HOXA5-induced apoptosis in breast cancer cells is mediated by caspase 2 and 8. Mol Cell Biol. 2004;24:924–935. PubMed PMC

Mansilla S, Priebe W, Portugal J. Mitotic catastrophe results in cell death by caspase-dependent and caspase-independent mechanisms. Cell Cycle. 2006;5:53–60. PubMed

Das S, Nwachukwu JC, Li D, Vulin AI, Martinez-Caballero S, Kinnally KW, Samuels HH. The nuclear receptor interacting factor-3 transcriptional coregulator mediates rapid apoptosis in breast cancer cells through direct and bystander-mediated events. Cancer Res. 2007;67:1775–1782. PubMed

The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes

Substituents at the C3' and C3'N positions are critical for taxanes to overcome acquired resistance of cancer cells to paclitaxel

Hedgehog pathway overexpression in pancreatic cancer is abrogated by new-generation taxoid SB-T-1216

The role of individual caspases in cell death induction by taxanes in breast cancer cells

Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells

Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes

Cell death induced by novel fluorinated taxanes in drug-sensitive and drug-resistant cancer cells