Combining Paclitaxel with ABT-263 Has a Synergistic Effect on Paclitaxel Resistant Prostate Cancer Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Mar 27

PMID 25811469

Citations 20

Authors

Chihuei Wang

Shih-Bo Huang

Min-Chi Yang

Yi-Tsen Lin

I-Hung Chu

Ya-Ni Shen

Yueh-Ho Chiu

Shao-Hung Hung

Lin Kang

Yi-Ren Hong

Chung-Hwan Chen

Affiliations

Soon will be listed here.

Abstract

We assessed the capability of paclitaxel, one of the taxanes, to induce death in two prostate cancer lines, LNCaP and PC3. Paclitaxel drove an apoptotic pathway in LNCaP, but not in PC3 cells, in response to G2/M arrest. An examination of the levels of anti-apoptotic proteins revealed that Bcl-xl was much higher in PC3 cells than in LNCaP cells and Bcl2 could be detected only in PC3 cells, not in LNCaP cells. Knocking down Bcl-xl enhanced paclitaxel-induced apoptosis in LNCaP cells, while we were unable to knock down Bcl-xl efficiently in PC3 cells. Significantly, a comparison of ABT-263, a specific inhibitor of Bcl2 and Bcl-xl, with ABT-199, a Bcl2 selective inhibitor, disclosed that only ABT-263, not ABT-199, could induce apoptosis in LNCaP and PC3 cells. The results indicate that Bcl-xl has a protective role against paclitaxel-induced apoptosis in LNCaP and PC3 cells, and its overexpression causes the paclitaxel resistance seen in PC3 cells. Interestingly, combined paclitaxel with ABT-263 to treat LNCaP and PC3 cells demonstrated synergistic apoptosis activation, indicating that ABT-263 could enhance paclitaxel-induced apoptosis in LNCaP cells and overcome Bcl-xl overexpression to trigger paclitaxel-induced apoptosis in PC3 cells. We also observed that the activation of apoptosis in LNCaP cells was more efficient than in PC3 cells in response to paclitaxel plus ABT-263 or to ABT-263 alone, suggesting that the apoptosis pathway in PC3 cells might have further differences from that in LNCaP cells even after Bcl-xl overexpression is accounted for.

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References

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

Ranganathan S, Benetatos C, Colarusso P, Dexter D, Hudes G . Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells. Br J Cancer. 1998; 77(4):562-6. PMC: 2149944. DOI: 10.1038/bjc.1998.91. View

Kroemer G, Galluzzi L, Brenner C . Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007; 87(1):99-163. DOI: 10.1152/physrev.00013.2006. View

Wilson W, OConnor O, Czuczman M, LaCasce A, Gerecitano J, Leonard J . Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010; 11(12):1149-59. PMC: 3025495. DOI: 10.1016/S1470-2045(10)70261-8. View

Janssen K, Pohlmann S, Janicke R, Schulze-Osthoff K, Fischer U . Apaf-1 and caspase-9 deficiency prevents apoptosis in a Bax-controlled pathway and promotes clonogenic survival during paclitaxel treatment. Blood. 2007; 110(10):3662-72. DOI: 10.1182/blood-2007-02-073213. View

Gogada R, Yadav N, Liu J, Tang S, Zhang D, Schneider A . Bim, a proapoptotic protein, up-regulated via transcription factor E2F1-dependent mechanism, functions as a prosurvival molecule in cancer. J Biol Chem. 2012; 288(1):368-81. PMC: 3537034. DOI: 10.1074/jbc.M112.386102. View

Vo T, Letai A . BH3-only proteins and their effects on cancer. Adv Exp Med Biol. 2010; 687:49-63. PMC: 3733261. DOI: 10.1007/978-1-4419-6706-0_3. View

Goncalves A, Braguer D, Kamath K, Martello L, Briand C, Horwitz S . Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics. Proc Natl Acad Sci U S A. 2001; 98(20):11737-42. PMC: 58799. DOI: 10.1073/pnas.191388598. View

Billard C . BH3 mimetics: status of the field and new developments. Mol Cancer Ther. 2013; 12(9):1691-700. DOI: 10.1158/1535-7163.MCT-13-0058. View

10.

van Delft M, Wei A, Mason K, Vandenberg C, Chen L, Czabotar P . The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006; 10(5):389-99. PMC: 2953559. DOI: 10.1016/j.ccr.2006.08.027. View

11.

Czabotar P, Lessene G, Strasser A, Adams J . Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2013; 15(1):49-63. DOI: 10.1038/nrm3722. View

12.

Souers A, Leverson J, Boghaert E, Ackler S, Catron N, Chen J . ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013; 19(2):202-8. DOI: 10.1038/nm.3048. View

13.

Kutuk O, Letai A . Alteration of the mitochondrial apoptotic pathway is key to acquired paclitaxel resistance and can be reversed by ABT-737. Cancer Res. 2008; 68(19):7985-94. PMC: 2603173. DOI: 10.1158/0008-5472.CAN-08-1418. View

14.

Hari M, Loganzo F, Annable T, Tan X, Musto S, Morilla D . Paclitaxel-resistant cells have a mutation in the paclitaxel-binding region of beta-tubulin (Asp26Glu) and less stable microtubules. Mol Cancer Ther. 2006; 5(2):270-8. DOI: 10.1158/1535-7163.MCT-05-0190. View

15.

Gaizo Moore V, Brown J, Certo M, Love T, Novina C, Letai A . Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007; 117(1):112-21. PMC: 1716201. DOI: 10.1172/JCI28281. View

16.

Kutuk O, Letai A . Displacement of Bim by Bmf and Puma rather than increase in Bim level mediates paclitaxel-induced apoptosis in breast cancer cells. Cell Death Differ. 2010; 17(10):1624-35. PMC: 2914832. DOI: 10.1038/cdd.2010.41. View

17.

Tse C, Shoemaker A, Adickes J, Anderson M, Chen J, Jin S . ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008; 68(9):3421-8. DOI: 10.1158/0008-5472.CAN-07-5836. View

18.

Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A . BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell. 2007; 12(2):171-85. DOI: 10.1016/j.ccr.2007.07.001. View

19.

Giannakakou P, Gussio R, Nogales E, Downing K, Zaharevitz D, Bollbuck B . A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proc Natl Acad Sci U S A. 2000; 97(6):2904-9. PMC: 16028. DOI: 10.1073/pnas.040546297. View

20.

Vogler M, Dinsdale D, Dyer M, Cohen G . Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ. 2008; 16(3):360-7. DOI: 10.1038/cdd.2008.137. View