This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Debernardis, D. Articles by Broggini, M. Search for Related Content PubMed PubMed Citation Articles by Debernardis, D. Articles by Broggini, M.

p53 Status Does Not Affect Sensitivity of Human Ovarian Cancer Cell Lines to Paclitaxel¹

Molecular Pharmacology Unit, LCP, Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri," via Eritrea, 62 20157 Milan [E. G. S. P. D. F. M. D., M. B.], and Department of Experimental Oncology, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova [D. D., F. V., M. V., P. R., S. P.], Italy

Nine human ovarian cancer cell lines that express wild-type (wt) or mutated p53 were used to evaluate the cytotoxicity induced by paclitaxel. The IC₅₀ calculated in the five mutated p53-expressing cell lines was not different from the four wt p53-expressing cell lines. The introduction of wt p53, by using a temperature-sensitive mutant murine p53 or the human p53 under the control of a tetracycline-dependent promoter, did not change the cytotoxicity of paclitaxel as compared to mock-transfected cells. By using for each cell line the paclitaxel IC₅₀, we found that these concentrations were sufficient to induce an increase in p53 levels in all of the four wt p53-expressing cells, whereas in the mutated p53-expressing cells, the levels were unaffected. This increase in p53 levels led to an increase in the mRNA and protein levels of p53 downstream genes (WAF1, GADD45, and bax). In none of the cell lines examined was paclitaxel able to induce apoptosis, evaluated by terminal deoxynucleotidyl transferase-mediated nick end labeling staining and filter binding assay at concentrations closed to the IC₅₀. By increasing the concentration of paclitaxel in the filter binding assay, we could see fragmentation of DNA in the different cell lines.

We conclude that the presence of p53 is not a determinant for the cytotoxicity induced by paclitaxel in human ovarian cancer cell lines. Differences in the activation of p53 downstream genes could be observed in wt versus mutated p53-expressing cells, but this does not account either for a differential induction of apoptosis or for a change in cytotoxicity induced by paclitaxel.

¹ This work was partially supported by Consiglio Nazionale delle Ricerche Progetto Finalizato Applicazioni Cliniche della Ricerca Oncologia Grants 95.00557-PF39, 95.00559-PF39, and 95.00447-PF39. The generous contribution of the Italian Association for Cancer Research is gratefully acknowledged. F. V. is a visiting scientist from the Institute of Cytology, Russian Academy of Science, St. Petersburg, Russia. D. D. received a fellowship from Associazione Italiana per la Ricerca sul Cancro. P. D. F. is a "fellow Famiglie Belloni e Guglielmetti."

² To whom requests for reprints should be addressed. Fax: 39-2-3546277; E-mail: broggini@irfmn.mnegri.it.

Received 8/12/96. Accepted 1/ 2/97.

This article has been cited by other articles:

				Q. Chang, D. Bhatia, Y. Zhang, T. Meighan, V. Castranova, X. Shi, and F. Chen Incorporation of an Internal Ribosome Entry Site-Dependent Mechanism in Arsenic-Induced GADD45{alpha} Expression Cancer Res., July 1, 2007; 67(13): 6146 - 6154. [Abstract] [Full Text] [PDF]

				F. Vikhanskaya, M. M. Siddique, M. Kei Lee, M. Broggini, and K. Sabapathy Evaluation of the Combined Effect of p53 Codon 72 Polymorphism and Hotspot Mutations in Response to Anticancer Drugs Clin. Cancer Res., June 15, 2005; 11(12): 4348 - 4356. [Abstract] [Full Text] [PDF]

				J. G. Teodoro, D. W. Heilman, A. E. Parker, and M. R. Green The viral protein Apoptin associates with the anaphase-promoting complex to induce G2/M arrest and apoptosis in the absence of p53 Genes & Dev., August 15, 2004; 18(16): 1952 - 1957. [Abstract] [Full Text] [PDF]

				A. Anelli, R. R. Brentani, A. P. Gadelha, A. Amorim de Albuquerque, and F. Soares Correlation of p53 status with outcome of neoadjuvant chemotherapy using paclitaxel and doxorubicin in stage IIIB breast cancer Ann. Onc., March 1, 2003; 14(3): 428 - 432. [Abstract] [Full Text] [PDF]

				P. Russo, D. Arzani, S. Trombino, and C. Falugi c-myc Down-Regulation Induces Apoptosis in Human Cancer Cell Lines Exposed to RPR-115135 (C31H29NO4), a Non-Peptidomimetic Farnesyltransferase Inhibitor J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 37 - 47. [Abstract] [Full Text] [PDF]

				P. B. Cassidy, P. J. Moos, R. C. Kelly, and F. A. Fitzpatrick Cyclooxygenase-2 Induction by Paclitaxel, Docetaxel, and Taxane Analogues in Human Monocytes and Murine Macrophages: Structure-Activity Relationships and Their Implications Clin. Cancer Res., March 1, 2002; 8(3): 846 - 855. [Abstract] [Full Text] [PDF]

				P. Russo, C. Ottoboni, D. Malacarne, A. Crippa, J.-F. Riou, and P. M. O'Connor Nonpeptidomimetic Farnesyltransferase Inhibitor RPR-115135 Increases Cytotoxicity of 5-Fluorouracil: Role of p53 J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 220 - 226. [Abstract] [Full Text] [PDF]

				G. Xu, J. Pan, C. Martin, and S.-C. J. Yeung Angiogenesis Inhibition in the in Vivo Antineoplastic Effect of Manumycin and Paclitaxel against Anaplastic Thyroid Carcinoma J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1769 - 1777. [Abstract] [Full Text]

				R. Perez-Soler, B. Kemp, Q. P. Wu, L. Mao, J. Gomez, A. Zeleniuch-Jacquotte, H. Yee, J. S. Lee, J. Jagirdar, and Y. H. Ling Response and Determinants of Sensitivity to Paclitaxel in Human Non-Small Cell Lung Cancer Tumors Heterotransplanted in Nude Mice Clin. Cancer Res., December 1, 2000; 6(12): 4932 - 4938. [Abstract] [Full Text]

				Y. Mitsuuchi, S. W. Johnson, M. Selvakumaran, S. J. Williams, T. C. Hamilton, and J. R. Testa The Phosphatidylinositol 3-Kinase/AKT Signal Transduction Pathway Plays a Critical Role in the Expression of p21WAF1/CIP1/SDI1 Induced by Cisplatin and Paclitaxel Cancer Res., October 1, 2000; 60(19): 5390 - 5394. [Abstract] [Full Text]

				G. Coukos, A. Makrigiannakis, E. H. Kang, S. C. Rubin, S. M. Albelda, and K. L. Molnar-Kimber Oncolytic Herpes Simplex Virus-1 Lacking ICP34.5 Induces p53-independent Death and Is Efficacious against Chemotherapy-resistant Ovarian Cancer Clin. Cancer Res., August 1, 2000; 6(8): 3342 - 3353. [Abstract] [Full Text]

				B. Kurdoglu, N. Cheong, J. Guan, B. W. Corn, W. J. Curran Jr., and G. Iliakis Apoptosis as a Predictor of Paclitaxel-induced Radiosensitization in Human Tumor Cell Lines Clin. Cancer Res., September 1, 1999; 5(9): 2580 - 2587. [Abstract] [Full Text] [PDF]

				B.-D. Chang, E. V. Broude, M. Dokmanovic, H. Zhu, A. Ruth, Y. Xuan, E. S. Kandel, E. Lausch, K. Christov, and I. B. Roninson A Senescence-like Phenotype Distinguishes Tumor Cells That Undergo Terminal Proliferation Arrest after Exposure to Anticancer Agents Cancer Res., August 1, 1999; 59(15): 3761 - 3767. [Abstract] [Full Text] [PDF]

				Z. A. Stewart, D. Mays, and J. A. Pietenpol Defective G1-S Cell Cycle Checkpoint Function Sensitizes Cells to Microtubule Inhibitor-induced Apoptosis Cancer Res., August 1, 1999; 59(15): 3831 - 3837. [Abstract] [Full Text] [PDF]

				P. L. Judson, J. M. Watson, P. A. Gehrig, W. C. Fowler Jr., and J. S. Haskill Cisplatin Inhibits Paclitaxel-induced Apoptosis in Cisplatin-resistant Ovarian Cancer Cell Lines: Possible Explanation for Failure ofCombination Therapy Cancer Res., May 1, 1999; 59(10): 2425 - 2432. [Abstract] [Full Text] [PDF]

				F. Vikhanskaya, G. Colella, M. Valenti, S. Parodi, M. D'Incalci, and M. Broggini Cooperation between p53 and hMLH1 in a Human Colocarcinoma Cell Line in Response to DNA Damage Clin. Cancer Res., April 1, 1999; 5(4): 937 - 941. [Abstract] [Full Text] [PDF]

				D. Polizzi, G. Pratesi, M. Tortoreto, R. Supino, A. Riva, E. Bombardelli, and F. Zunino A Novel Taxane with Improved Tolerability and Therapeutic Activity in a Panel of Human Tumor Xenografts Cancer Res., March 1, 1999; 59(5): 1036 - 1040. [Abstract] [Full Text] [PDF]

				P. J. Moos and F. A. Fitzpatrick Taxane-mediated gene induction is independent of microtubule stabilization: Induction of transcription regulators and enzymes that modulate inflammation and apoptosis PNAS, March 31, 1998; 95(7): 3896 - 3901. [Abstract] [Full Text] [PDF]