Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1997;75(3):333–340. doi: 10.1038/bjc.1997.55

Multifactorial mechanism for the potentiation of cisplatin (CDDP) cytotoxicity by all-trans retinoic acid (ATRA) in human ovarian carcinoma cell lines.

M J Caliaro 1, P Vitaux 1, C Lafon 1, I Lochon 1, A Néhmé 1, A Valette 1, P Canal 1, R Bugat 1, S Jozan 1
PMCID: PMC2063358  PMID: 9020476

Abstract

All-trans retinoic acid (ATRA) has been previously shown to inhibit the proliferation of some human ovarian carcinoma cell lines, and this inhibition was accompanied by cellular changes that were indicative of differentiation (Caliaro et al, 1994). In this work, a pretreatment of these adenocarcinoma cells with ATRA, for their respective doubling time, enhanced cisplatin (CDDP) cytotoxicity in the cell ines that were sensitive to its antiproliferative effect, but not in the ATRA-resistant ones. Results were assessed using median effect analysis in two ATRA-sensitive cell lines (OVCCR1 and NIHOVCAR3 cells) and in one ATRA-insensitive cell line (IGROV1 cells). Synergy between these two agents was observed only in cells sensitive to ATRA, regardless of their relative sensitivity to CDDP. Potential mechanisms for this synergy were investigated. ATRA did not increase the cellular platinum content, did not decrease the cellular glutathione and had no influence on the metallothionein IIA mRNA levels in NIHOVCAR3 cells. Moreover, the protein kinase C (PKC) activity was modulated by this differentiating agent in all cell lines tested, indicating that this activity was not directly involved in this potentiation. However, an ATRA inhibition of glutathione-S-transferase activity associated with an increase in the total DNA adducts formation could explain the potentiation of the CDDP cytotoxicity observed in NIHOVCAR3 cells. Finally, the ATRA modulation of the epidermal growth factor (EGF) receptor mRNA level could also be implicated in this synergy.

Full text

PDF
333

Images in this article

338Figure 7
on p.338

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akerboom T. P., Sies H. Assay of glutathione, glutathione disulfide, and glutathione mixed disulfides in biological samples. Methods Enzymol. 1981;77:373–382. doi: 10.1016/s0076-6879(81)77050-2. [DOI] [PubMed] [Google Scholar]
  2. Andrews P. A., Schiefer M. A., Murphy M. P., Howell S. B. Enhanced potentiation of cisplatin cytotoxicity in human ovarian carcinoma cells by prolonged glutathione depletion. Chem Biol Interact. 1988;65(1):51–58. doi: 10.1016/0009-2797(88)90030-0. [DOI] [PubMed] [Google Scholar]
  3. Basu A., Evans R. W. Comparison of effects of growth factors and protein kinase C activators on cellular sensitivity to cis-diamminedichloroplatinum(II). Int J Cancer. 1994 Aug 15;58(4):587–591. doi: 10.1002/ijc.2910580423. [DOI] [PubMed] [Google Scholar]
  4. Bedford P., Fichtinger-Schepman A. M., Shellard S. A., Walker M. C., Masters J. R., Hill B. T. Differential repair of platinum-DNA adducts in human bladder and testicular tumor continuous cell lines. Cancer Res. 1988 Jun 1;48(11):3019–3024. [PubMed] [Google Scholar]
  5. Behrens B. C., Hamilton T. C., Masuda H., Grotzinger K. R., Whang-Peng J., Louie K. G., Knutsen T., McKoy W. M., Young R. C., Ozols R. F. Characterization of a cis-diamminedichloroplatinum(II)-resistant human ovarian cancer cell line and its use in evaluation of platinum analogues. Cancer Res. 1987 Jan 15;47(2):414–418. [PubMed] [Google Scholar]
  6. Benchekroun M. N., Parker R., Reed E., Sinha B. K. Inhibition of DNA repair and sensitization of cisplatin in human ovarian carcinoma cells by interleukin-1 alpha. Biochem Biophys Res Commun. 1993 Aug 31;195(1):294–300. doi: 10.1006/bbrc.1993.2044. [DOI] [PubMed] [Google Scholar]
  7. Bouzinba-Segard H., Fan X. T., Perderiset M., Castagna M. Synergy between phorbol esters and retinoic acid in inducing protein kinase C activation. Biochem Biophys Res Commun. 1994 Oct 14;204(1):112–119. doi: 10.1006/bbrc.1994.2433. [DOI] [PubMed] [Google Scholar]
  8. Caliaro M. J., Marmouget C., Guichard S., Mazars P., Valette A., Moisand A., Bugat R., Jozan S. Response of four human ovarian carcinoma cell lines to all-trans retinoic acid: relationship with induction of differentiation and retinoic acid receptor expression. Int J Cancer. 1994 Mar 1;56(5):743–748. doi: 10.1002/ijc.2910560522. [DOI] [PubMed] [Google Scholar]
  9. Castaigne S., Chomienne C., Daniel M. T., Ballerini P., Berger R., Fenaux P., Degos L. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 1990 Nov 1;76(9):1704–1709. [PubMed] [Google Scholar]
  10. Chen G., Frei E., Zeller W. J. Determination of intracellular reduced glutathione and glutathione related enzyme activities in cisplatin-sensitive and resistant experimental ovarian carcinoma cell lines. Cancer Lett. 1989 Aug;46(3):207–211. doi: 10.1016/0304-3835(89)90132-8. [DOI] [PubMed] [Google Scholar]
  11. Chou T. C., Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55. doi: 10.1016/0065-2571(84)90007-4. [DOI] [PubMed] [Google Scholar]
  12. Christen R. D., Hom D. K., Porter D. C., Andrews P. A., MacLeod C. L., Hafstrom L., Howell S. B. Epidermal growth factor regulates the in vitro sensitivity of human ovarian carcinoma cells to cisplatin. J Clin Invest. 1990 Nov;86(5):1632–1640. doi: 10.1172/JCI114885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Doyle L. A., Giangiulo D., Hussain A., Park H. J., Yen R. W., Borges M. Differentiation of human variant small cell lung cancer cell lines to a classic morphology by retinoic acid. Cancer Res. 1989 Dec 1;49(23):6745–6751. [PubMed] [Google Scholar]
  14. Dukas K., Sarfati P., Vaysse N., Pradayrol L. Quantitation of changes in the expression of multiple genes by simultaneous polymerase chain reaction. Anal Biochem. 1993 Nov 15;215(1):66–72. doi: 10.1006/abio.1993.1555. [DOI] [PubMed] [Google Scholar]
  15. Formelli F., Cleris L. Synthetic retinoid fenretinide is effective against a human ovarian carcinoma xenograft and potentiates cisplatin activity. Cancer Res. 1993 Nov 15;53(22):5374–5376. [PubMed] [Google Scholar]
  16. Guchelaar H. J., Timmer-Bosscha H., Dam-Meiring A., Uges D. R., Oosterhuis J. W., de Vries E. G., Mulder N. H. Enhancement of cisplatin and etoposide cytotoxicity after all-trans retinoic-acid-induced cellular differentiation of a murine embryonal carcinoma cell line. Int J Cancer. 1993 Sep 30;55(3):442–447. doi: 10.1002/ijc.2910550320. [DOI] [PubMed] [Google Scholar]
  17. Habig W. H., Pabst M. J., Jakoby W. B. Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem. 1974 Nov 25;249(22):7130–7139. [PubMed] [Google Scholar]
  18. Heniford B. W., Shum-Siu A., Leonberger M., Hendler F. J. Variation in cellular EGF receptor mRNA expression demonstrated by in situ reverse transcriptase polymerase chain reaction. Nucleic Acids Res. 1993 Jul 11;21(14):3159–3166. doi: 10.1093/nar/21.14.3159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hirata J., Kikuchi Y., Kita T., Imaizumi E., Tode T., Ishii K., Kudoh K., Nagata I. Modulation of sensitivity of human ovarian cancer cells to cis-diamminedichloroplatinum(II) by 12-O-tetradecanoylphorbol-13-acetate and D,L-buthionine-S,R-sulphoximine. Int J Cancer. 1993 Sep 30;55(3):521–527. doi: 10.1002/ijc.2910550332. [DOI] [PubMed] [Google Scholar]
  20. Hofmann J., Doppler W., Jakob A., Maly K., Posch L., Uberall F., Grunicke H. H. Enhancement of the antiproliferative effect of cis-diamminedichloroplatinum(II) and nitrogen mustard by inhibitors of protein kinase C. Int J Cancer. 1988 Sep 15;42(3):382–388. doi: 10.1002/ijc.2910420313. [DOI] [PubMed] [Google Scholar]
  21. Howell S. B., Kirmani S., McClay E. F., Kim S., Braly P., Plaxe S. Intraperitoneal cisplatin-based chemotherapy for ovarian carcinoma. Semin Oncol. 1991 Feb;18(1 Suppl 3):5–10. [PubMed] [Google Scholar]
  22. Isonishi S., Andrews P. A., Howell S. B. Increased sensitivity to cis-diamminedichloroplatinum(II) in human ovarian carcinoma cells in response to treatment with 12-O-tetradecanoylphorbol 13-acetate. J Biol Chem. 1990 Mar 5;265(7):3623–3627. [PubMed] [Google Scholar]
  23. Jozan S., Roché H., Cheutin F., Carton M., Salles B. New human ovarian cell line OVCCR1/sf in serum-free medium. In Vitro Cell Dev Biol. 1992 Nov-Dec;28A(11-12):687–689. doi: 10.1007/BF02631049. [DOI] [PubMed] [Google Scholar]
  24. Kurie J. M., Younes A., Miller W. H., Jr, Burchert M., Chiu C. F., Kolesnick R., Dmitrovsky E. Retinoic acid stimulates the protein kinase C pathway before activation of its beta-nuclear receptor during human teratocarcinoma differentiation. Biochim Biophys Acta. 1993 Nov 7;1179(2):203–207. doi: 10.1016/0167-4889(93)90142-c. [DOI] [PubMed] [Google Scholar]
  25. Le-Ruppert K., Masters J. R., Knuechel R., Seegers S., Tainsky M. A., Hofstaedter F., Buettner R. The effect of retinoic acid on chemosensitivity of PA-1 human teratocarcinoma cells and its modulation by an activated N-ras oncogene. Int J Cancer. 1992 Jun 19;51(4):646–651. doi: 10.1002/ijc.2910510423. [DOI] [PubMed] [Google Scholar]
  26. Mann S. C., Andrews P. A., Howell S. B. Modulation of cis-diamminedichloroplatinum(II) accumulation and sensitivity by forskolin and 3-isobutyl-1-methylxanthine in sensitive and resistant human ovarian carcinoma cells. Int J Cancer. 1991 Jul 30;48(6):866–872. doi: 10.1002/ijc.2910480613. [DOI] [PubMed] [Google Scholar]
  27. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Morikage T., Ohmori T., Nishio K., Fujiwara Y., Takeda Y., Saijo N. Modulation of cisplatin sensitivity and accumulation by amphotericin B in cisplatin-resistant human lung cancer cell lines. Cancer Res. 1993 Jul 15;53(14):3302–3307. [PubMed] [Google Scholar]
  29. Nehmé A., Albin N., Caliaro M. J., Guichard S., Jozan S., Julia A. M., Bugat R., Canal P. Mechanism of interaction between cisplatin and human recombinant interferon gamma in human ovarian-cancer cell lines. Int J Cancer. 1995 May 29;61(5):643–648. doi: 10.1002/ijc.2910610510. [DOI] [PubMed] [Google Scholar]
  30. Nishikawa K., Rosenblum M. G., Newman R. A., Pandita T. K., Hittelman W. N., Donato N. J. Resistance of human cervical carcinoma cells to tumor necrosis factor correlates with their increased sensitivity to cisplatin: evidence of a role for DNA repair and epidermal growth factor receptor. Cancer Res. 1992 Sep 1;52(17):4758–4765. [PubMed] [Google Scholar]
  31. Ozols R. F., Young R. C. Chemotherapy of ovarian cancer. Semin Oncol. 1991 Jun;18(3):222–232. [PubMed] [Google Scholar]
  32. Reed E., Ozols R. F., Tarone R., Yuspa S. H., Poirier M. C. Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy. Proc Natl Acad Sci U S A. 1987 Jul;84(14):5024–5028. doi: 10.1073/pnas.84.14.5024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sacks P. G., Harris D., Chou T. C. Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: a rationale for combination therapy with chemotherapeutic agents. Int J Cancer. 1995 May 4;61(3):409–415. doi: 10.1002/ijc.2910610322. [DOI] [PubMed] [Google Scholar]
  34. Sporn M. B., Roberts A. B. Role of retinoids in differentiation and carcinogenesis. Cancer Res. 1983 Jul;43(7):3034–3040. [PubMed] [Google Scholar]
  35. Xia C., Taylor J. B., Spencer S. R., Ketterer B. The human glutathione S-transferase P1-1 gene: modulation of expression by retinoic acid and insulin. Biochem J. 1993 Jun 15;292(Pt 3):845–850. doi: 10.1042/bj2920845. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES