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Adriamycin (ADM) induced apoptosis in Transitional Cell Cancer (TCC) cell lines accompanied by p21 WAF1/CIP1 induction

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Abstract

Genotoxic stimuli, including anticancer drugs, induce apoptosis in cancer cells through increase of p53, p21WAF1/CIP1 , at least in part. Bcl-2 and Bax modify this pathway or directly regulated by p53. Here we studied Adriamycin (ADM)-induced apoptosis in four human bladder cancer cell lines in respect of p53, p21WAF1/CIP1 and Bcl-2 family proteins. After ADM, treatment bladder cancer cells underwent dose-dependent cell death with typical morphologic features of apoptosis. Among four cell lines RT4 with wt p53, low ratio of Bcl-2 to Bax and induction of p21WAF1/CIP1 after ADM treatment, was the most sensitive to induction of apoptosis. Thus, p53, p21WAF1/CIP1 , Bcl-2 and Bax status might determine susceptibility of bladder cancer cells to ADM induced apoptosis.

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References

  1. Lundbeck F, Bruun E, Finnerup B, Christophersen IS. Intravesical therapy of noninvasive bladder tumors (stage Ta) with doxorubicin: initial treatment results and the long-term course. J Urol 1988; 139: 1212–1213.

    Google Scholar 

  2. Nakada T, Akiya T, Yoshikawa M, Koike H, Kayayama T. Intravesical instillation of doxorubicin hydrochloride and its incorporation into bladder tumors. J Urol 1985; 134: 54–57.

    Google Scholar 

  3. Schulman CC, Wespes E, Delcour C, Struyven J. Intra-arterial chemotherapy of infiltrative bladder carcinoma. Eur Urol 1985; 11: 220–223.

    Google Scholar 

  4. Mimnaugh EG, Trush MA, Bhatnagar M, Gram TE. Enhancement of reactive oxygen-dependent mitochondrial membrane lipid peroxydation by the anticancer adriamycin. Biochem Pharmacol 1985; 34: 847–856.

    Google Scholar 

  5. Eliot H, Gianni L, Myers C. Oxidative destruction of DNA by the adriamycin-iron complex. Biochemistry 1984; 23: 928–936.

    Google Scholar 

  6. Muindi JRF, Sinha BK, Gianni L, Myers CE. Hydroxyl radical production and DNA damage induced by anthracycline-iron complex. FEBS Lett 1984; 172: 226–230.

    Google Scholar 

  7. Muindi JRF, Sinha BK, Gianni L, Myers CE. Thiol-dependent DNA damage produced by anthracycline-iron complex: the structure-activity relationships and molecular mechanisms. Mol Pharmacol 1985; 27: 356–365.

    Google Scholar 

  8. Biedler JL. Drug resistance: genotype versus phenotype. 32nd G. H. A. Clowes Memorial Award Lecture. Cancer Res 1994; 54: 666–678.

    Google Scholar 

  9. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991; 253: 49–53.

    Google Scholar 

  10. Mietz JA, Unger T, Huibregtse JM, Howley PM. The transcriptional transactivation function of wild-type p53 is inhibited by SV40 large T-antigen and by HPV-16 E6 oncoprotein. EMBO J 1992; 11: 5013–5020.

    Google Scholar 

  11. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992; 69: 1237–1245.

    Google Scholar 

  12. El-Deiry WS, Tokino T, Velkulesku VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817–825.

    Google Scholar 

  13. Miyashita T, Krajewski S, Krajewska M, et al. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 1994; 9: 1799–1805.

    Google Scholar 

  14. Oltvai ZN, Millman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates cell death. Cell 1993; 74: 609–619.

    Google Scholar 

  15. Boise LH, Gonzalez-Garcia M, Postema CE, et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993; 74: 597–608.

    Google Scholar 

  16. Bilim V, Tomita Y, Kawasaki T, Katagiri A, Imai T, Takeda M, Takahashi K. Prognostic value of Bcl-2 and p53 expression in urinary tract transitional cell cancer [Letter]. JNCI 1996; 88: 686–688.

    Google Scholar 

  17. Kawasaki T, Tomita Y, Watanabe R, Tanikawa T, Kumanishi T, Sato S. mRNA and protein expression of p53 mutations in human bladder cancer cell lines. Cancer Lett 1994; 82: 113–121.

    Google Scholar 

  18. Kawasaki T, Tomita Y, Bilim V, Takeda M, Takahashi K, Kumanishi T. Abrogation of apoptosis induced by DNA-damaging agents in human bladder-cancer cell lines with p21/WAF1/CIP1 an/or p53 gene alterations. Int J Cancer 1996; 68: 501–505.

    Google Scholar 

  19. Blin N, Stafford DW. A general method for isolation of high molecular weight DNA from eucaryotes. Nucleic Acids Res 1976; 3: 2303–2308.

    Google Scholar 

  20. Tomita Y, Bilim V, Kawasaki T, Okan I, Magnusson KP, Wiman KG. Frequent expression of Bcl-2 in renal-cell carcinomas carrying wild-type p53. Int J Cancer 1996; 66: 322–325.

    Google Scholar 

  21. Tomita Y, Saito T, Saito K, Oite T, Shimizu F, Sato S. Possible significance of VLA-4 (a4 b1) for hematogenous metastasis of renal cell cancer. Int J Cancer 1995; 60: 753–758.

    Google Scholar 

  22. Mossmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxic assays. J Immuno Methods 1983; 65: 55–63.

    Google Scholar 

  23. Tomita Y, Kawasaki T, Bilim V, Takeda M, Takahashi K. Tetrapeptide DEVD-aldehyde or YVAD-chloromethylketone inhibits Fas/Apo-1 (CD95)-mediated apoptosis in renal-cell-cancer cells. Int J Cancer 1996; 68: 132–135.

    Google Scholar 

  24. Watanabe R, Tomita Y, Nishiyama T, Tanikawa T, Sato S. Correlation of p53 protein expression in human urothelial transitional cell cancers with malignant potential and patient survival. Int J Urol 1994; 1: 43–48.

    Google Scholar 

  25. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991; 51: 6304–6311.

    Google Scholar 

  26. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 1992; 89: 7491–7495.

    Google Scholar 

  27. El-Deiry WS, Harper JW, O'Connor PM, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 1994; 54: 1169–1174.

    Google Scholar 

  28. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinase. Cell 1993; 75: 805–816.

    Google Scholar 

  29. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature 1993; 366: 701–704.

    Google Scholar 

  30. Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 1992; 356: 215–221.

    Google Scholar 

  31. Miyashita T, Reed JC. bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res 1992; 52: 5407–5411.

    Google Scholar 

  32. Miyashita T, Reed JC. Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 1993; 81: 151–157.

    Google Scholar 

  33. Selvakumaran M, Lin HK, Miyashita T, et al. Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. Oncogene 1994; 9: 1791–1798.

    Google Scholar 

  34. Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res 1994; 54: 3131–3135.

    Google Scholar 

  35. Kimiya K, Naito S, Soejima T, et al. Establishment and characterization of doxorubicin-resistant human bladder cancer cell line, KK47/ADM. J Urol 1992; 148: 441–445.

    Google Scholar 

  36. Naito S, Sakamoto N, Kotoh S, Matsumoto T, Kumazawa J. Correlation between the expression of P-glycoprotein and multi-drug-resistant phenotype in transitional cell carcinoma of the urinary tract. Eur Urol 1992; 22: 158–162.

    Google Scholar 

  37. Shinohara N, Liebert M, Wedemeyer G, Chang JHC, Grossman HB. Evaluation of multidrug resistance in human bladder cancer cell lines. J Urol 1993; 150: 505–509.

    Google Scholar 

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Authors and Affiliations

  1. Department of Urology, Niigata University School of Medicine, Asahimachi 1, Niigata, Japan

    V. N. Bilim, Y. Tomita, T. Kawasaki, M. Takeda & K. Takahashi

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  1. V. N. Bilim
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  2. Y. Tomita
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  3. T. Kawasaki
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  4. M. Takeda
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  5. K. Takahashi
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Bilim, V.N., Tomita, Y., Kawasaki, T. et al. Adriamycin (ADM) induced apoptosis in Transitional Cell Cancer (TCC) cell lines accompanied by p21 WAF1/CIP1 induction. Apoptosis 2, 207–213 (1997). https://doi.org/10.1023/A:1026472700554

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