1 Eye 2007 Vol: 22(3):454-460. DOI: 10.1038/sj.eye.6702764

Beta-lapachone inhibits proliferation and induces apoptosis in retinoblastoma cell lines

Eye is the official journal of the Royal College of Ophthalmologists. It aims to provide the practising ophthalmologist with information on the latest clinical and laboratory-based research.

Mentions
Figures
Figure 1: Growth inhibitory effects of beta-lapachone in RB cell lines at 96 h post-treatment. The IC50 of beta-lapachone was 1.3 M in Weri-RB1 cells, 0.9 M in RBM cells, and 1.9 M in Y79 cells. Figure 2: Growth inhibitory effects of etoposide in Y79 cells at 96 h post-treatment. The IC50 of etoposide was 1.2 M, which was similar to the IC50 of beta-lapachone in this cell line. Figure 3: Caspase 3/7 activation in Y79 cells treated with 1.9 M beta-lapachone. Beta-lapachone induced apoptosis-associated caspase 3/7 activity, which increased to 3.5 times vehicle-treated control values at 72 h post-treatment on average. Figure 4: Cytoplasmic nucleosome enrichment in Y79 cells treated with 1.9 M beta-lapachone. Beta-lapachone induced apoptosis-associated intranucleosomal fragmentation, which increased to 5.6 times vehicle-treated control values at 96 h post-treatment on average. Figure 5: Apoptotic cellular morphology detected by Hoechst staining in Y79 cells treated with 1.9 M beta-lapachone. Beta-lapachone increased the mean per cent of apoptotic cell bodies in Y79 cultures to 1.7 times vehicle-treated control values at 48-h post-treatment. The mean per cent of apoptotic cells at this time point was 26.03.8 and 9.70.3% (meanSD) in treated and control cultures, respectively. Figure 6: Beta-lapachone-treated Y79 cells demonstrating apoptotic cellular morphology (arrows) by Hoechst staining. Cells were treated with 1.9 M beta-lapachone for 48 h.
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References
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    • . . . Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood, affecting 1 in 15 000 children.1 The disease is caused by loss of function of both alleles of the RB tumour suppressor gene (RB1) in retinal progenitor cells . . .
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    • . . . These children typically develop bilateral, multifocal retinal tumours, and they are also predisposed to develop second primary tumours later in life, particularly bone and soft-tissue sarcomas.2 RB also occurs in a nonheritable form, in which biallelic inactivation of RB1 occurs somatically in a single retinoblast . . .
    • . . . External beam radiotherapy induces midfacial hypoplasia, retinopathy, optic neuropathy, early cataract formation, and increased incidence of second tumours within the radiation field in children with heritable RB.2, 4, 5 For this reason, chemotherapy with local therapy has become the preferred treatment option for this disease in recent years.6 The current standard chemotherapeutic regimen for RB includes carboplatin, etoposide, and vincristine (CEV) . . .
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    • . . . An overall survival rate between 90 and 95% can be achieved with combinations of chemotherapy, external beam radiotherapy, plaque radiotherapy, laser photocoagulation, cryotherapy, and enucleation.3 In the developing world, however, RB remains a frequently fatal disease. . . .
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    • . . . External beam radiotherapy induces midfacial hypoplasia, retinopathy, optic neuropathy, early cataract formation, and increased incidence of second tumours within the radiation field in children with heritable RB.2, 4, 5 For this reason, chemotherapy with local therapy has become the preferred treatment option for this disease in recent years.6 The current standard chemotherapeutic regimen for RB includes carboplatin, etoposide, and vincristine (CEV) . . .
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    • . . . External beam radiotherapy induces midfacial hypoplasia, retinopathy, optic neuropathy, early cataract formation, and increased incidence of second tumours within the radiation field in children with heritable RB.2, 4, 5 For this reason, chemotherapy with local therapy has become the preferred treatment option for this disease in recent years.6 The current standard chemotherapeutic regimen for RB includes carboplatin, etoposide, and vincristine (CEV) . . .
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    • . . . External beam radiotherapy induces midfacial hypoplasia, retinopathy, optic neuropathy, early cataract formation, and increased incidence of second tumours within the radiation field in children with heritable RB.2, 4, 5 For this reason, chemotherapy with local therapy has become the preferred treatment option for this disease in recent years.6 The current standard chemotherapeutic regimen for RB includes carboplatin, etoposide, and vincristine (CEV) . . .
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    • . . . These agents have been associated with adverse effects in some patients including febrile episodes, cytopenia, neutropenia, infections, gastrointestinal distress, and vincristine neurotoxicity.7, 8, 9, 10, 11 Etoposide and carboplatin are also mutagenic . . .
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    • . . . These agents have been associated with adverse effects in some patients including febrile episodes, cytopenia, neutropenia, infections, gastrointestinal distress, and vincristine neurotoxicity.7, 8, 9, 10, 11 Etoposide and carboplatin are also mutagenic . . .
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    • . . . These agents have been associated with adverse effects in some patients including febrile episodes, cytopenia, neutropenia, infections, gastrointestinal distress, and vincristine neurotoxicity.7, 8, 9, 10, 11 Etoposide and carboplatin are also mutagenic . . .
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    • . . . These agents have been associated with adverse effects in some patients including febrile episodes, cytopenia, neutropenia, infections, gastrointestinal distress, and vincristine neurotoxicity.7, 8, 9, 10, 11 Etoposide and carboplatin are also mutagenic . . .
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    • . . . These agents have been associated with adverse effects in some patients including febrile episodes, cytopenia, neutropenia, infections, gastrointestinal distress, and vincristine neurotoxicity.7, 8, 9, 10, 11 Etoposide and carboplatin are also mutagenic . . .
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    • . . . Etoposide therapy is associated with risk for acute myelocytic leukaemia,12 and secondary leukaemias have so far been reported in two RB patients treated with etoposide.13, 14 Carboplatin may also act synergistically with etoposide in the induction of secondary leukaemias.15, 16 Because these agents are mutagenic, both of these drugs have potential to exacerbate second tumour risk in children with heritable disease. . . .
  13. Nishimura S, Sato T, Ueda H, Ueda K. Acute myeloblastic leukemia as a second malignancy in a patient with hereditary retinoblastoma. J Clin Oncol 2001; 19: 4182-4183 , .
    • . . . Etoposide therapy is associated with risk for acute myelocytic leukaemia,12 and secondary leukaemias have so far been reported in two RB patients treated with etoposide.13, 14 Carboplatin may also act synergistically with etoposide in the induction of secondary leukaemias.15, 16 Because these agents are mutagenic, both of these drugs have potential to exacerbate second tumour risk in children with heritable disease. . . .
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    • . . . Etoposide therapy is associated with risk for acute myelocytic leukaemia,12 and secondary leukaemias have so far been reported in two RB patients treated with etoposide.13, 14 Carboplatin may also act synergistically with etoposide in the induction of secondary leukaemias.15, 16 Because these agents are mutagenic, both of these drugs have potential to exacerbate second tumour risk in children with heritable disease. . . .
  15. Travis LB, Holowaty EJ, Bergfeldt K, Lynch CF, Kohler BA, Wiklund T et al. Risk of leukemia after platinum-based chemotherapy for ovarian cancer. N Engl J Med 1999; 340: 351-357 , .
    • . . . Etoposide therapy is associated with risk for acute myelocytic leukaemia,12 and secondary leukaemias have so far been reported in two RB patients treated with etoposide.13, 14 Carboplatin may also act synergistically with etoposide in the induction of secondary leukaemias.15, 16 Because these agents are mutagenic, both of these drugs have potential to exacerbate second tumour risk in children with heritable disease. . . .
  16. Griesinger F, Metz M, Trumper L, Schulz T, Haase D. Secondary leukaemia after cure for locally advanced NSCLC: alkylating type secondary leukaemia after induction therapy with docetaxel and carboplatin for NSCLC IIIB. Lung Cancer 2004; 44: 261-265 , .
    • . . . Etoposide therapy is associated with risk for acute myelocytic leukaemia,12 and secondary leukaemias have so far been reported in two RB patients treated with etoposide.13, 14 Carboplatin may also act synergistically with etoposide in the induction of secondary leukaemias.15, 16 Because these agents are mutagenic, both of these drugs have potential to exacerbate second tumour risk in children with heritable disease. . . .
  17. Li YZ, Li CJ, Pinto AV, Pardee AB. Release of mitochondrial cytochrome c in both apoptosis and necrosis induced by beta-lapachone in human carcinoma cells. Mol Med 1999; 5: 232-239 , .
    • . . . This agent induces potent cytotoxic effects in a wide variety of malignant human cell types, including colon, lung, prostate, breast, pancreatic, ovarian, and bone cancers, as well as leukaemia, melanoma, and malignant glioma.17, 18, 19, 20, 21, 22 Beta-lapachone appears to exert a spectrum of anticancer effects, resulting in both apoptotic20, 23, 24 and necrotic17, 19 cell death . . .
    • . . . Beta-lapachone can directly inhibit DNA topoisomerases I and II,25, 26 and induce G1- and/or S-phase cell-cycle delay followed by apoptosis or necrosis.17, 18, 23 Beta-lapachone cytotoxicity may also be mediated by the activity of the NAD(P)H:quinone oxidoreductase enzyme NQO1.27 This agent has also been shown to selectively induce apoptosis in breast and prostate cancer cells but not in untransformed cells through a mechanism that appears to involve selective induction of the transcription factor E2F1, a regulator of both S-phase progression and apoptosis.24 To our knowledge, the effects of beta-lapachone in RB cell lines have not yet been investigated. . . .
    • . . . In the present study, beta-lapachone induced dose-dependent growth inhibition at low micromolar concentrations in all three RB cell lines tested, consistent with observations in other cancer cell lines.17, 18, 19, 20, 21, 22 We subsequently confirmed that growth inhibition was mediated, at least in part, by induction of apoptosis, as indicated by increased caspase 3/7 activity and intranucleosomal fragmentation . . .
  18. Li CJ, Li YZ, Pinto AV, Pardee AB. Potent inhibition of tumor survival in vivo by beta-lapachone plus taxol: combining drugs imposes different artificial checkpoints. Proc Natl Acad Sci USA 1999; 96: 13369-13374 , .
    • . . . This agent induces potent cytotoxic effects in a wide variety of malignant human cell types, including colon, lung, prostate, breast, pancreatic, ovarian, and bone cancers, as well as leukaemia, melanoma, and malignant glioma.17, 18, 19, 20, 21, 22 Beta-lapachone appears to exert a spectrum of anticancer effects, resulting in both apoptotic20, 23, 24 and necrotic17, 19 cell death . . .
    • . . . In the present study, beta-lapachone induced dose-dependent growth inhibition at low micromolar concentrations in all three RB cell lines tested, consistent with observations in other cancer cell lines.17, 18, 19, 20, 21, 22 We subsequently confirmed that growth inhibition was mediated, at least in part, by induction of apoptosis, as indicated by increased caspase 3/7 activity and intranucleosomal fragmentation . . .
    • . . . Although our experiments were limited to evaluating the cytotoxic effects of beta-lapachone alone in RB cells, a number of studies have found significant synergistic effects of beta-lapachone with other chemotherapeutic agents.18, 35, 36, 37 Beta-lapachone induces G1/S checkpoint delay before inducing cell death, and remarkable in vitro and in vivo synergistic effects have been observed when this agent is administered in combination with taxol, which arrests cells in G2/M.18 Beta-lapachone has also been reported to enhance the cytotoxicity of alkylating agents in vitro, possibly owing to beta-lapachone-induced inhibition of DNA repair.37 Other studies have demonstrated that beta-lapachone can be effective as a single agent in cross-resistant cell lines.30, 38 The chemosensitizing effects of beta-lapachone could have application in the clinical management of RB, where chemotherapeutic resistance is frequently observed . . .
    • . . . In one study of a mouse model of human ovarian cancer, beta-lapachone administered intraperitoneally in an oil-based vehicle at doses up to 50 mg/kg (10 cycles, q.o.d.) induced significant antitumour effects with no reported systemic toxicity.18 Consistent yet more complete toxicity data have been reported in normal mice receiving intraperitoneal injections of beta-lapachone in beta-cyclodextrin inclusion complexes on a similar schedule.40 No toxicity was observed in mice treated with 50 mg/kg beta-lapachone in beta-cyclodextrin/water . . .
  19. Liu TJ, Lin SY, Chau YP. Inhibition of poly(ADP-ribose) polymerase activation attenuates beta-lapachone-induced necrotic cell death in human osteosarcoma cells. Toxicol Appl Pharmacol 2002; 182: 116-125 , .
    • . . . This agent induces potent cytotoxic effects in a wide variety of malignant human cell types, including colon, lung, prostate, breast, pancreatic, ovarian, and bone cancers, as well as leukaemia, melanoma, and malignant glioma.17, 18, 19, 20, 21, 22 Beta-lapachone appears to exert a spectrum of anticancer effects, resulting in both apoptotic20, 23, 24 and necrotic17 . . .
    • . . . In the present study, beta-lapachone induced dose-dependent growth inhibition at low micromolar concentrations in all three RB cell lines tested, consistent with observations in other cancer cell lines.17, 18, 19, 20, 21, 22 We subsequently confirmed that growth inhibition was mediated, at least in part, by induction of apoptosis, as indicated by increased caspase 3/7 activity and intranucleosomal fragmentation . . .
  20. Planchon SM, Wuerzberger S, Frydman B, Witiak DT, Hutson P, Church DR et al. Beta-lapachone-mediated apoptosis in human promyelocytic leukemia (HL-60) and human prostate cancer cells: a p53-independent response. Cancer Res 1995; 55: 3706-3711 , .
    • . . . This agent induces potent cytotoxic effects in a wide variety of malignant human cell types, including colon, lung, prostate, breast, pancreatic, ovarian, and bone cancers, as well as leukaemia, melanoma, and malignant glioma.17, 18, 19, 20, 21, 22 Beta-lapachone appears to exert a spectrum of anticancer effects, resulting in both apoptotic20, 23, 24 and necrotic17, 19 cell death . . .
    • . . . In the present study, beta-lapachone induced dose-dependent growth inhibition at low micromolar concentrations in all three RB cell lines tested, consistent with observations in other cancer cell lines.17, 18, 19, 20, 21, 22 We subsequently confirmed that growth inhibition was mediated, at least in part, by induction of apoptosis, as indicated by increased caspase 3/7 activity and intranucleosomal fragmentation . . .
  21. Chau YP, Shiah SG, Don MJ, Kuo ML. Involvement of hydrogen peroxide in topoisomerase inhibitor beta-lapachone-induced apoptosis and differentiation in human leukemia cells. Free Radic Biol Med 1998; 24: 660-670 , .
    • . . . This agent induces potent cytotoxic effects in a wide variety of malignant human cell types, including colon, lung, prostate, breast, pancreatic, ovarian, and bone cancers, as well as leukaemia, melanoma, and malignant glioma.17, 18, 19, 20, 21, 22 Beta-lapachone appears to exert a spectrum of anticancer effects, resulting in both apoptotic20, 23, 24 and necrotic17, 19 cell death . . .
    • . . . In the present study, beta-lapachone induced dose-dependent growth inhibition at low micromolar concentrations in all three RB cell lines tested, consistent with observations in other cancer cell lines.17, 18, 19, 20, 21, 22 We subsequently confirmed that growth inhibition was mediated, at least in part, by induction of apoptosis, as indicated by increased caspase 3/7 activity and intranucleosomal fragmentation . . .
  22. Weller M, Winter S, Schmidt C, Esser P, Fontana A, Dichgans J et al. Topoisomerase-I inhibitors for human malignant glioma: differential modulation of p53, p21, bax and bcl-2 expression and of CD95-mediated apoptosis by camptothecin and beta-lapachone. Int J Cancer 1997; 73: 707-714 , .
    • . . . This agent induces potent cytotoxic effects in a wide variety of malignant human cell types, including colon, lung, prostate, breast, pancreatic, ovarian, and bone cancers, as well as leukaemia, melanoma, and malignant glioma.17, 18, 19, 20, 21, 22 Beta-lapachone appears to exert a spectrum of anticancer effects, resulting in both apoptotic20, 23, 24 and necrotic17, 19 cell death . . .
    • . . . In the present study, beta-lapachone induced dose-dependent growth inhibition at low micromolar concentrations in all three RB cell lines tested, consistent with observations in other cancer cell lines.17, 18, 19, 20, 21, 22 We subsequently confirmed that growth inhibition was mediated, at least in part, by induction of apoptosis, as indicated by increased caspase 3/7 activity and intranucleosomal fragmentation . . .
  23. Wuerzberger SM, Pink JJ, Planchon SM, Byers KL, Bornmann WG, Boothman DA. Induction of apoptosis in MCF-7:WS8 breast cancer cells by beta-lapachone. Cancer Res 1998; 58: 1876-1885 , .
    • . . . This agent induces potent cytotoxic effects in a wide variety of malignant human cell types, including colon, lung, prostate, breast, pancreatic, ovarian, and bone cancers, as well as leukaemia, melanoma, and malignant glioma.17, 18, 19, 20, 21, 22 Beta-lapachone appears to exert a spectrum of anticancer effects, resulting in both apoptotic20, 23, 24 and necrotic17, 19 cell death . . .
  24. Li Y, Sun X, LaMont JT, Pardee AB, Li CJ. Selective killing of cancer cells by beta-lapachone: direct checkpoint activation as a strategy against cancer. Proc Natl Acad Sci USA 2003; 100: 2674-2678 , .
    • . . . This agent induces potent cytotoxic effects in a wide variety of malignant human cell types, including colon, lung, prostate, breast, pancreatic, ovarian, and bone cancers, as well as leukaemia, melanoma, and malignant glioma.17, 18, 19, 20, 21, 22 Beta-lapachone appears to exert a spectrum of anticancer effects, resulting in both apoptotic20, 23, 24 and necrotic17, 19 cell death . . .
    • . . . Beta-lapachone can directly inhibit DNA topoisomerases I and II,25, 26 and induce G1- and/or S-phase cell-cycle delay followed by apoptosis or necrosis.17, 18, 23 Beta-lapachone cytotoxicity may also be mediated by the activity of the NAD(P)H:quinone oxidoreductase enzyme NQO1.27 This agent has also been shown to selectively induce apoptosis in breast and prostate cancer cells but not in untransformed cells through a mechanism that appears to involve selective induction of the transcription factor E2F1, a regulator of both S-phase progression and apoptosis.24 To our knowledge, the effects of beta-lapachone in RB cell lines have not yet been investigated. . . .
    • . . . Beta-lapachone has recently been reported to induce apoptosis selectively in breast and colon cancer cells, but not in untransformed breast or colon epithelial cells.24 Low micromolar concentrations of beta-lapachone have also been observed to profoundly inhibit proliferation of myeloma cells with no apparent effect on normal peripheral blood mononuclear cells at the same concentrations, further indicating an unusual selectivity of beta-lapachone against cancer cells.30 . . .
    • . . . The induction of apoptosis in breast and colon cancer cells by beta-lapachone has been reported to involve selective and rapid induction of the cell-cycle regulating factor, E2F1.24 E2F1 is one of the ‘activating’ members of the E2F family of transcription factors, which, along with E2F2 and E2F3, can induce a large set of genes required for S-phase progression.31, 32 E2F1 has been found to regulate both cellular proliferation and apoptosis, depending on the levels of E2F1 expressed . . .
  25. Li CJ, Averboukh L, Pardee AB. Beta-lapachone, a novel DNA topoisomerase I inhibitor with a mode of action different from camptothecin. J Biol Chem 1993; 268: 22463-22468 , .
    • . . . Beta-lapachone can directly inhibit DNA topoisomerases I and II,25, 26 and induce G1- and/or S-phase cell-cycle delay followed by apoptosis or necrosis.17, 18, 23 Beta-lapachone cytotoxicity may also be mediated by the activity of the NAD(P)H:quinone oxidoreductase enzyme NQO1.27 This agent has also been shown to selectively induce apoptosis in breast and prostate cancer cells but not in untransformed cells through a mechanism that appears to involve selective induction of the transcription factor E2F1, a regulator of both S-phase progression and apoptosis.24 To our knowledge, the effects of beta-lapachone in RB cell lines have not yet been investigated. . . .
  26. Frydman B, Marton LJ, Sun JS, Neder K, Witiak DT, Liu AA et al. Induction of DNA topoisomerase II-mediated DNA cleavage by beta-lapachone and related naphthoquinones. Cancer Res 1997; 57: 620-627 , .
    • . . . Beta-lapachone can directly inhibit DNA topoisomerases I and II,25, 26 and induce G1- and/or S-phase cell-cycle delay followed by apoptosis or necrosis.17, 18, 23 Beta-lapachone cytotoxicity may also be mediated by the activity of the NAD(P)H:quinone oxidoreductase enzyme NQO1.27 This agent has also been shown to selectively induce apoptosis in breast and prostate cancer cells but not in untransformed cells through a mechanism that appears to involve selective induction of the transcription factor E2F1, a regulator of both S-phase progression and apoptosis.24 To our knowledge, the effects of beta-lapachone in RB cell lines have not yet been investigated. . . .
  27. Pink JJ, Planchon SM, Tagliarino C, Varnes ME, Siegel D, Boothman DA. NAD(P)H: quinone oxidoreductase activity is the principal determinant of beta-lapachone cytotoxicity. J Biol Chem 2000; 275: 5416-5424 , .
  28. Malorni W, Fais S, Fiorentini C. Morphological Aspects of Apoptosis. In: A Cossarizza and D Boraschi (eds). Apoptosis: A Laboratory Manual of Experimental Methods, Available on-line in The Purdue Cytometry CD-ROM Vol 4, J Watson, Guest Ed. JP Robinson, Purdue University Cytometry Laboratories: West Lafayette, IN, 1997. Link , .
    • . . . For each time point, a representative chamber was selected, and all cells in that chamber were counted and categorized by morphological appearance according to previously described criteria28 (http://www.cyto.purdue.edu/cdroms/flow/vol4/index.htm) . . .
    • . . . In addition, beta-lapachone-treated Y79 RB cells displayed cellular morphology characteristic of apoptosis, including chromatin condensation, nuclear fragmentation with bleb formation, and pyknotic bodies28 (http://www.cyto.purdue.edu/cdroms/flow/vol4/index.htm) . . .
  29. Conway RM, Madigan MC, Penfold PL, Billson FA. Induction of apoptosis by sodium butyrate in the human Y-79 retinoblastoma cell line. Oncol Res 1995; 7: 289-297 , .
  30. Gupta D, Podar K, Tai YT, Lin B, Hideshima T, Akiyama M et al. Beta-lapachone, a novel plant product, overcomes drug resistance in human multiple myeloma cells. Exp Hematol 2002; 30: 711-720 , .
  31. Nahle Z, Polakoff J, Davuluri RV, McCurrach ME, Jacobson MD, Narita M et al. Direct coupling of the cell cycle and cell death machinery by E2F. Nat Cell Biol 2002; 4: 859-864 , .
  32. Trimarchi JM, Lees JA. Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 2002; 3: 11-20 , .
    • . . . The induction of apoptosis in breast and colon cancer cells by beta-lapachone has been reported to involve selective and rapid induction of the cell-cycle regulating factor, E2F1.24 E2F1 is one of the ‘activating’ members of the E2F family of transcription factors, which, along with E2F2 and E2F3, can induce a large set of genes required for S-phase progression.31, 32 E2F1 has been found to regulate both cellular proliferation and apoptosis, depending on the levels of E2F1 expressed . . .
  33. Ginsberg D. E2F1 pathways to apoptosis. FEBS Lett 2002; 529: 122-125 , .
  34. Planchon SM, Pink JJ, Tagliarino C, Bornmann WG, Varnes ME, Boothman DA. Beta-lapachone-induced apoptosis in human prostate cancer cells: involvement of NQO1/xip3. Exp Cell Res 2001; 267: 95-106 , .
    • . . . Other studies in prostate and breast cancer cells have reported that beta-lapachone-induced apoptosis can occur through a mechanism involving NQOI-mediated cycling of this agent.27, 34, 35 NQOI is an enzyme that reduces quinone-containing agents such as beta-lapachone to more reactive forms . . .
  35. Kumi-Diaka J, Saddler-Shawnette S, Aller A, Brown J. Potential mechanism of phytochemical-induced apoptosis in human prostate adenocarcinoma cells: Therapeutic synergy in genistein and beta-lapachone combination treatment. Cancer Cell Int 2004; 4: 5 , .
    • . . . Other studies in prostate and breast cancer cells have reported that beta-lapachone-induced apoptosis can occur through a mechanism involving NQOI-mediated cycling of this agent.27, 34, 35 NQOI is an enzyme that reduces quinone-containing agents such as beta-lapachone to more reactive forms . . .
    • . . . Although our experiments were limited to evaluating the cytotoxic effects of beta-lapachone alone in RB cells, a number of studies have found significant synergistic effects of beta-lapachone with other chemotherapeutic agents.18, 35, 36, 37 Beta-lapachone induces G1/S checkpoint delay before inducing cell death, and remarkable in vitro and in vivo synergistic effects have been observed when this agent is administered in combination with taxol, which arrests cells in G2/M.18 Beta-lapachone has also been reported to enhance the cytotoxicity of alkylating agents in vitro, possibly owing to beta-lapachone-induced inhibition of DNA repair.37 Other studies have demonstrated that beta-lapachone can be effective as a single agent in cross-resistant cell lines.30, 38 The chemosensitizing effects of beta-lapachone could have application in the clinical management of RB, where chemotherapeutic resistance is frequently observed . . .
  36. Boorstein RJ, Pardee AB. Beta-lapachone greatly enhances MMS lethality to human fibroblasts. Biochem Biophys Res Commun 1984; 118: 828-834 , .
    • . . . Although our experiments were limited to evaluating the cytotoxic effects of beta-lapachone alone in RB cells, a number of studies have found significant synergistic effects of beta-lapachone with other chemotherapeutic agents.18, 35, 36, 37 Beta-lapachone induces G1/S checkpoint delay before inducing cell death, and remarkable in vitro and in vivo synergistic effects have been observed when this agent is administered in combination with taxol, which arrests cells in G2/M.18 Beta-lapachone has also been reported to enhance the cytotoxicity of alkylating agents in vitro, possibly owing to beta-lapachone-induced inhibition of DNA repair.37 Other studies have demonstrated that beta-lapachone can be effective as a single agent in cross-resistant cell lines.30, 38 The chemosensitizing effects of beta-lapachone could have application in the clinical management of RB, where chemotherapeutic resistance is frequently observed . . .
  37. Boothman DA, Trask DK, Pardee AB. Inhibition of potentially lethal DNA damage repair in human tumor cells by beta-lapachone, an activator of topoisomerase I. Cancer Res 1989; 49: 605-612 , .
    • . . . Although our experiments were limited to evaluating the cytotoxic effects of beta-lapachone alone in RB cells, a number of studies have found significant synergistic effects of beta-lapachone with other chemotherapeutic agents.18, 35, 36, 37 Beta-lapachone induces G1/S checkpoint delay before inducing cell death, and remarkable in vitro and in vivo synergistic effects have been observed when this agent is administered in combination with taxol, which arrests cells in G2/M.18 Beta-lapachone has also been reported to enhance the cytotoxicity of alkylating agents in vitro, possibly owing to beta-lapachone-induced inhibition of DNA repair.37 Other studies have demonstrated that beta-lapachone can be effective as a single agent in cross-resistant cell lines.30, 38 The chemosensitizing effects of beta-lapachone could have application in the clinical management of RB, where chemotherapeutic resistance is frequently observed . . .
  38. Dolan ME, Frydman B, Thompson CB, Diamond AM, Garbiras BJ, Safa AR et al. Effects of 1,2-naphthoquinones on human tumor cell growth and lack of cross-resistance with other anticancer agents. Anticancer Drugs 1998; 9: 437-448 , .
    • . . . Although our experiments were limited to evaluating the cytotoxic effects of beta-lapachone alone in RB cells, a number of studies have found significant synergistic effects of beta-lapachone with other chemotherapeutic agents.18, 35, 36, 37 Beta-lapachone induces G1/S checkpoint delay before inducing cell death, and remarkable in vitro and in vivo synergistic effects have been observed when this agent is administered in combination with taxol, which arrests cells in G2/M.18 Beta-lapachone has also been reported to enhance the cytotoxicity of alkylating agents in vitro, possibly owing to beta-lapachone-induced inhibition of DNA repair.37 Other studies have demonstrated that beta-lapachone can be effective as a single agent in cross-resistant cell lines.30, 38 The chemosensitizing effects of beta-lapachone could have application in the clinical management of RB, where chemotherapeutic resistance is frequently observed . . .
  39. Park HJ, Ahn KJ, Ahn SD, Choi E, Lee SW, Williams B et al. Susceptibility of cancer cells to beta-lapachone is enhanced by ionizing radiation. Int J Radiat Oncol Biol Phys 2005; 61: 212-219 , .
  40. Nasongkla N, Wiedmann AF, Bruening A, Beman M, Ray D, Bornmann WG et al. Enhancement of solubility and bioavailability of beta-lapachone using cyclodextrin inclusion complexes. Pharm Res 2003; 20: 1626-1633 , .
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