臺灣博碩士論文加值系統

I. Tryptanthrin衍生物誘發MCF7細胞凋亡之探討
Tryptanthrin(indolo[2,1-b]quinazolin-6,12-dione)為含N-phenyl quinazoline的四環共面結構，具有類似2- phenylnaphthalene的結構，已被發現廣泛存於各種活性化合物中，若非共平面結構則使活性降低或甚至喪失。例如具2-phenylquinolone結構的抗癌化合物batracylin，可毒殺多種癌細胞。由於不同的取代基會表現出不同的生物活性及效價，因此本論文的目的在於篩選與分析tryptanthrin衍生物的細胞凋亡活性，作為抗癌藥物的可能性。在細胞毒性試驗中，我們發現一些tryptanthrin衍生物，如：DQ181、DQ166、EY093都具細胞毒性，而且它們不只是在癌細胞MCF7，在HeLa, A498和SKOV3等細胞株也都具有不同程度的細胞毒性。我們在實驗中也證實了引起細胞的死亡方式為細胞凋亡，其中MCF7對tryptanthrin衍生物的敏感性最大，而DQ181的細胞毒性效價最高，因此我們推測DQ181具有發展成為抗乳癌藥物的潛力。此外我們進一步確認它們的凋亡機制，發現DQ181藉由調節Fas receptor和Fas ligand的表現來活化caspase-8蛋白質酉每 引起的細胞凋亡作用，其中Fas receptor 蛋白質表現量在加藥後兩小時增加，但隨即降低，而Fas ligand蛋白質表
現量則是隨著加藥後的時間而增加。
II. Tryptanthrin衍生物DQ181抑制TCDD誘發多環芳香烴類受器的轉位
TCDD為2,3,7,8-四氯聯苯戴奧辛和其類似物都會引起廣泛的生化、毒性反應或者是致癌。TCDD和多環芳香烴類受器結合後會轉移至細胞核內，與ARNT形成二聚物後結合在特定基因的促進子上，促進基因的大量轉錄；這些基因包括了細胞色素P450s(CYPs)，因此通常CYP1A1 mRNA的大量表現與否便可以利用來篩選出多環芳香烴類受器的ligand。我們的結果證實tryptanthrin衍生物DQ181可以有效抑制TCDD所引起的CYP1A1 mRNA的大量表現，並且進一步的發現DQ181是藉由拮抗或穩定AhR-Hsp90複合物來阻止多環芳香烴類受器從細胞質轉移至細胞核，因此抑制CYP1A1 mRNA的大量表現。

I. The apoptotic activity of tryptanthrin derivatives in MCF7 cells
Tryptanthrin, indolo[2,1-b]quinazolin-6,12-dione, is a coplanar four-fused ring compound which contains N-phenyl-quinazoline skeleton similar to 2-phenyl-naphthalene. It was illustrated that compounds containing coplanar 2-phenyl-naphthalene skeleton exhibit different biological activites, while the bioactivities would be decreased or lost in unplanar structures. For example, batracylin, containing 2-phenyl-quinolone skeleton,inhibits the growth of carcinoma cell lines. In previous data, tryptanthrin derivatives with different substituents exert different potency of various bioactivities. It draws our attention to screen tryptanthrin derivatives for cytotoxicity and study their apoptotic activity as potential anticancer agents. In the cytotoxic assay, tryptanthrin derivatives, DQ181, DQ166 and EY093, exert cytotoxic activity in cancer cell lines including MCF7, HeLa, A498, SKOV3 cells. Our data showed that cells undergo apoptosis and die. MCF7 cells are the most sensitive to these tryptanthrin derivatives. DQ181 is the most potent compound of those tryptanthrin derivatives. The result suggested that DQ181 may be a new compound developed to treat breast cancer. We further study the mechanism of apoptosis induced by DQ181. The extensive experiments indicated DQ181-induced apoptosis may be via upregulation of the expression of Fas receptor and Fas ligand, resulting in activating caspase-8 mediated pathway.
Fas receptor protein overexpresses in two hours but decrease later. Fas ligand protein expression stimulated by DQ181 was elevated in a time dependent manner。
II. Inhibition of TCDD-induced aryl hydrocarbon receptor
translocation by tryptanthrin derivative DQ181
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds induce a broad spectrum of biochemical and toxic responses including carcinogenesis. Binding of TCDD to Ah receptor is followed by AhR transport to the nucleus, dimerization with the aryl hydrocarbon nuclear translocator (ARNT), and transcription of a potentially large number of genes containing AhR complex-binding sequences in their promoter regions. Genes encoding cytochrome P450s(CYPs) enzymes are regarded as AhR-regulated genes. Induction of cytochrome P1A1 mRNA is a sensitive marker of AhR—ligand interaction. Our result demonstrates that tryptanthrin derivative DQ181 can inhibit TCDD-induced cytochrome P1A1 mRNA expression regarding to blocking or stablizing AhR-Hsp90 complex followed by inhibition of translocation from cytosol to nuclear. It may interfere with cytochrome P450 1A1-related carcinogenesis.

目 錄
壹、緒論-------------------------------------------------1
I. Tryptanthrin衍生物誘發MCF7細胞凋亡之探討
一、Tryptanthrin衍生物
二、細胞凋亡 (Apoptosis)
(1)細胞凋亡的定義
(2)細胞淍亡的特徵
(3)細胞淍亡與細胞壞死的差異
(4)細胞淍亡的調控
(5)Caspase的活化
三、細胞週期 (Cell cycle)
II. Tryptanthrin衍生物DQ181抑制TCDD誘發多環芳香烴類受
器的轉位
一、多環芳香烴類受器 (Aryl hydrocarbon receptor)
二、2,3,7,8-四氯聯苯戴奧辛 (TCDD)
三、Cytochrome P1A1 (CYP1A1)
貳、實驗材料與方法-------------------------------------------11
第一節實驗材料
第二節實驗方法
一、細胞株的培養
二、MTT 試驗
三、DNA片段分析
四、以流式細胞計數儀分析細胞凋亡與細胞週期
五、逆轉錄-聚合酵素連鎖反應法 (RT-PCR)
六、西方點漬法 (Western blotting)
七、Caspase試驗
參、結果------------------------------------------------------23
一、Tryptanthrin衍生物的細胞毒性篩選
二、Tryptanthrin衍生物引起人類癌細胞株的凋亡作用
三、Tryptanthrin和其衍生物引起人類癌細胞株的生長週期異常
四、DQ181引起的凋亡路徑
五、加入DQ181對細胞內Fas receptor/ligand的mRNA表現量的影響
六、加入DQ181對細胞內Fas receptor/ligand的蛋白質量的影響
七、DQ181抑制Ah receptor mediated CYP1A1 mRNA的表現
八、DQ181抑制TCDD引起Ah receptor在細胞質和細胞核之間的轉移
肆、討論------------------------------------------------------48
I. Tryptanthrin衍生物誘發MCF7細胞凋亡之探討
一、Tryptanthrin衍生物的細胞毒性篩選
二、Tryptanthrin衍生物引起人類癌細胞株的凋亡作用與細胞週期異常
三、DQ181引起的凋亡路徑
II. Tryptanthrin衍生物DQ181抑制TCDD誘發多環芳香烴類受
器的轉位
伍、結論------------------------------------------------------54
陸、參考文獻---------------------------------------- ---------56

參考文獻
1. Bergman J., Egestad B., Lindstrom J.-O., The structure of
some indolic constituents
in Couroupita Guaianensis Aubl. Tetrahedron Lett., 1977, 30,
2625-2626.
2. Jarrah M. Y., Thaller V., 300MHz Hnmr spectra of indolo[2,1-
b] quinazoline-6,12-
dione, tryptanthrine and its 2- and 8-chloro- derivatives.
J. Chem. Res. 1980,186.
3. Brufani M., Fedeli W., Mazza F., Gerhard A., Keller-
Schierlein W., The structure of
tryptanthrin. Experientia, 1971,27,1249-1250.
4. Mitscher L. A., Wong W.-C., DeMeulenaere T., Sulko J., Drake
S., Antimicrobial agents from higher plants. NEW synthesis
and bioactivity of tryptanthrin (indolo- [2,1-b]-quinazolin-6,12-dione) and its analogues. Heterocycle, 1981, 15(2). 1017-
1021.
5. Mitscher L. A., and Baker W., A search for novelchemotherapy
against tuberculosis amongst natural products. Pure&Appl.
Chem. 1998, 70(2), 365-371.
6. Mitscher L. A., Baker W., Tuberculosis:A search for novel
therapy starting with natural products. Med. Res. Rev. 18,
1998, 6, 363-374.
7. Wall M. E.; Wanai M. C., Cook C. E., Palmer K. H., McPhail
A. T., Sim G. A, Plant antitumor agents. I the isolation and
structure of camptothecin, a novel alkaloidal leukemia and
tumor inhibitors from Camptotheca acuminata. J Am. Chem.
Soc. 1966. 88. 3888-3890.
8. Meegalla S.K., Stevens G. J., Hochstein F. A., The synthesis
of ellipticine. J. Am. Chem. Soc. 1959. 81. 4434-4435.
9. Boise L. H., Gonzalez-Garcia M., Postema C. E., Ding L.,
Lindsten T., Turka L. A., and Hockenbery D. Defining
apoptosis. Am. J.Pathol. 1995. 146. 16-19.
10. Agnes B. Am. J. Pathol., Kane. Redefining cell death.
1995. 146. 1-2.
11. Williams G. T. and Smith C. A. Molecular regulation of
apoptosis:genetic controls on cell death. Cell. Cell. 1993.
74. 777-779.
12. Reed J. C. Mechanisms of apoptosis avoidance in cancer.
Curr Opin Oncol. 1999. 11. 68-75.
13. Andrew H. W. Apoptosis and carcinogenesis. Eur J. Cell
Biol. 1997. 73. 189-197.
14. Fraser A., and Evan, G.,A license to kill. Cell. 1996. 85.
781-784.
15. Leach A. P. Apoptosis and carcinogenesis. Eur J. Cell Biol.
1997. 73. 189-197.
16. Kerr J. F. R., Winterford C. M., and Harmon B. V.
Apoptosis. Cancer. 1994. 73. 2013-2016.
17. Leist M., Nicotera P. Apoptosis versus necrosis: the shape
of neuronal cell death. Results Probl. Cell Differ. 1997.
24. 105-135.
18. Kerr, J. F. R., Winterford C. M., Harmon, B.V. Apoptosis.
Cancer. 1994. 73. 2013-2016
19. Gerald M. C. Caspases:the executioners of apoptosis. Cell.
1999. 96. 245-254.
20. Douglas K. M. The role of the caspase family of cysteine
proteases in apoptosis. Seminars in Immunol. 1997. 9. 35-49.
21. David L. V., Stanley,J K. Cell Death in development.
Cell.1999. 96. 245-254.
22. Gabriel N., Mary A. B., Yuanmimg Hu., and Naohiro, I.
Caspase:the proteases of the apoptotic pathway. Oncogene.
1998. 17. 3237-3245.
23. Nancy A. T., Yuri L., Caspsaes:enmies within. Science.
1998. 281. 1312-1316.
24. Timothy S. Z., Stephane H., Richard A. F., Yuri l.
Deficiency in caspase-9 or caspase-3 induces compensatory
caspase activation. Nature. 2000. 6. 1241-1247.
25. Inohara, N., Koseki, T., Chen, S., Benedict M. A., Nunez.
G. Identification regulatory and catalytic domains in the
apoptosis nuclease DFF40/CAD. J. Biol.Chem. 1999. 274. 270-
274.
26. Kim, N, View point:putting cell cycle in order. Science.
1997. 274. 1643-1645.
27. Bruce S. Cell cycle control of DNA replication. Science,
1997. 274. 1659-1664.
28. Mark E. H., The aryl hydrocarbon receptor:A comparative
perspective. Comparative biochemistry and physiology-part
C:pharmacology, toxicology and endocrinology 1998. 121. 23-
53.
29. James P. Whitlock, Jr. The Aromatic hydrocarbon receptor,
dioxin Action, and endocrine homeostasis.TIBS. 1994. 5. 183-
188.
30. The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator
(ARNT) heterodimer interactswith naturally occurring
estrogen response elements. Mol. & Cell. Endo. 1999. 157(1-
2). 105-119.
31. Ellen C., Henry A. S., George R., Michael J., Thomas A.,
Jeffrey P. J., Flavone antagonists bind competitively with
2,3,7,8-tetrachloro dibenzo-p-dioxin(TCDD) to the aryl
hydrocarbon receptor but inhibit nuclear uptake and
transformation. 1999. 85. 102-133.
32. Qiang Ma, Anthony J. Renzelli, Kimberly T. Baldwin, and
James M. Antonini, Superinduction of CYP1A1 Gene
Expression. The Jounal of Biological Chemistry. 2000. 275.
12676—12683.
33. O. Dohr, C. Vogel, J. Abel, Different response of 2,3,7,8-
tetra chlorodibenzo-p-dioxin(TCDD)-sensitive genes in human
breast cancer MCF-7 and MDA-MB 231 cells. Arch. Bioch.
Biophy. 1995. 321. 405-412.
34. Alaa F.Badawi, Ercole L.Cavalieri and Eleanor G.Rogan.
Effect of chlorinated hydrocarbons on expression of
cytochrome P450 1A1, 1A2 and 1B1 and 2- and 4-hydroxylation
of 17b-estradiol in female Sprague- Dawley rats. 2000. 21.
1593-1599.
35. Seidel A. D., Rogers W. J., Winter G. M., Nichael S.,
Eugenio I., Ah receptor-based chemical screening
bioassays:application and limitations for the detection of
ah receptor agonists. Toxicological Sciences. 2000. 55. 107-
115.
36. Yi-Zhong Gu, John B. Hogenesch, and Christopher A., Effect
of curcumin on the aryl hydrocarbon receptor and cytochrome
P450 1A1 in MCF7 human breast carcinoma cells. Bioch.
Pharmacol. 1998. 56. 197-206.
37. Jennifer V. S., Gloria H.-T., Christopher A. B., Simon M.
C., Characterization of a murine Ahr null
allele:involvement of the Ah receptor in hepatic growth and
development. Proc. Natl. Acad. Sci. USA. 1996. 93. 6731-
6736.
38. Wei L., Donat S., Klaus U., Josef Abel, Ah receptor in
different tissues of C57BL/6J and DBA/ 2J Mice: use of
competitive polymerase chain reaction to measure Ah-
receptor mRNA expression. Arch. Bioch. Biophy. 1994. 315.
279-284.
39. Kennedy S. W., Jones S. P., Simultaneous Measurement of
cytochrome P4501A catalytic activity and total protein
concentration with a fluorescence plate reader.Anal. Bioch.
1994. 222. 217-223.
40. Olaf Dohr, Christoph Vogel, Josef Abel, Different response
of 2,3,7,8 -tetrachlorodibenzo-p-dioxin(TCDD)-sensitive
genes in human breast cancer MCF-7 and MDA-MB 231 cells.
Arch. Bioch. Biophy. 1995. 321. 405-412.
41. Michael E. B., Hseuh-Kung L., Trevor M. P., Isoform-
specific induction of a human aldo-keto reductase by
polycyclic aromatic hydrocarbons(PAHs), Electrophiles, and
oxidative stress: implications for the alternative pathway
of PAH activation catalyzed by human dihydrodiol
dehydrogenase. Cancer Res. 1999. 59. 607-614.
42. Frank J., Gonzalez and Kenneth R. Korzekwa., Cytochromes
P450 expression systems. Annu. Rev. Pharmacol. Toxicol.
1995. 35. 369-390.
43. Plomley J.-B., Lausevic M., March R.-E., Determination of
dioxins/furans and PCBs by quadrupole ion-trap gas
chromatography-mass spectrometry. Mass Spectrometry
Reviews. 2000. 19. 305-65.
44. Seta N., Arfi C., Momas I., General population exposure to
dioxins, human ubiquitous pollutants. Revue d Epidemiologie
et de Sante Publique. 2000. 48. 281-93.
45. Michael Schwarz, Albrecht Buchmann, Stefan Stinchcombe,
Arno Kalkuhl, Karl-Walter Bock,Ah receptor ligands and
tumor promotion:survival of neoplastic cells. Toxicology.
2000. 112-113. 69-77.
46. Ichen Chen, Andrew McDougal, Fan Wang, Stephen Safe, Aryl
hydrocarbon receptor-mediated antiestrogenic and
antitumorigenic activity of diindolylmethane
Carcinogenesis. 1998. 19. 1631-1639.
47. Liem A. K., Furst P., Rappe C., Exposure of populations to
dioxins and related compounds. Food Additives &
Contaminants. 2000. 17. 241-259.
48. Geneva Switzerland, Executive Summary-Assessment of the
health risk of dioxins: re-evaluation of the Tolerable
Daily Intake(TDI)，WHO European Centre for Environment and
Health. 1998. 25-29.
49. The US EPA Dioxin Exposure Initiative, National Center For
Environment Assessment. USEPA. 1999. 5.
50. Furst P., Rappe C., Dioxin: A Technical Review. SEPA. 1998.
51. Delescluse, G. Lemaire, G. De Sousa, R. Rahmani, Is CYP1A1
induction always related to AHR signaling pathway?
Toxicology. 2000.153. 73-82.
52. Christine S., Pierre L., Narbonne J.-F., Carpy A.,
Molecular characteristics of carbaryl, a CYP1A1 gene
inducer. Arch. Bioch. Biophy. 2000. 373. 275-280.
53. Anttila S., Lei XD., Elovaara E., Karjalainen A., Sun W.,
Vainio H., Hankinson O., An uncommon phenotype of poor
inducibility of CYP1A1 in human lung is not ascribable to
polymorphisms in the AHR, ARNT, or CYP1A1 genes.
Pharmacogenetics. 2000. 10. 741-51.
54. Barouki R., Morel Y., Repression of cytochrome P450 1A1
gene expression by oxidative stress: mechanisms and
biological implications. Biochemical Pharmacology. 2001. 61
(5). 511-6.
55. Vistica DT. Skehan P. Scudiero D. Monks A. Pittman A. Boyd
MR. Tetrazolium- based assays for cellular viability:a
critical examination of selected parameters affecting
formazan production. Cancer Res. 1991. 51. 2515-2520.
56. Darzynkiewicz Z. Gong J. Traganos F. Analysis of DNA
content and cyclin protein expression in studies of DNA
ploidy,growth fraction, lymphocyte stimulation, and the
cell cycle. Methods in Cell Biology. 1994. 41. 421-35.
57. Bertrand R. Sarang M. Jenkin J. Kerrigan D. Pommier Y.
Differential induction of secondary DNA fragmentation by
topoisomerase II inhibitors in human tumor cell lines with
amplified c-myc expression. Cancer Res. 1991. 51. 6280-6285.
58. Bertrand R. Solary E. Jenkins J. Pommier Y. Apoptosis and
its modulation in human promyelocytic HL-60 cells treated
with DNA topoisomerase I and II inhibitors. Experimental
Cell Research. 1993. 207(2). 388-397.
59. Slee EA, Adrain C, Martin SJ, Serial killers:ordering
caspase activation events in apoptosis. Cell death & diff.
1999. 6. 1067-1074.
60. Nicholson D. W., Thornberry N. A., Caspases:Killer
proteases. TIBS. 1996. 22. 229-237.
61. Mitra G., Riss T., CasACETM Assay system, Fluorometric.
Cell Sgnaling. 1998. 66. 7-14.
62. Kumar S., Lavin M. F., The ICE family of cysteine proteases
as effectors of cell death. Cell Death Diff. 1996. 2. 255-
230.
63. Debatin K.-M.,Activation of apoptosis pathways by
anticancer treatment. Toxicol. Letters. 2000. 112-113. 41-
48.
64. Morimoto Y., Haneji T., Kito S., Upregulation of the
expression of fas antigen and fas ligand in a human
submandibular gland ductal cell line by okadaic acid.
Arch.Oral Bio. 2000. 45. 657-666.
65. Honglin L., Hong Z., Chi-jie X., Junying Y. Cleavage of bid
by caspase 8 mediates the mitochondrial damage in fas
pathway of apoptosis. Cell. 1998. 94. 491-501.
66. Jon Nilsen, Gil Mor, Frederick Naftolin, Estrogen-Regulated
Developmental Neuronal Apoptosis Is Determined by Estrogen
Receptor Subtype and the Fas/Fas Ligand System. Neurobiol.
2000. 43. 64-78.
67. Schrenk D., Riebniger D., Till M., Fiedler H.-P.,
Tryptanthrin:A novel class of agonists of the aryl
hydrocarbon receptor. Biochem. Pharmacol. 1997. 54. 165-171.
68. John J., Jing-yu L., Russell E., David T., Dudley P.,
PD98059 is an equipotent antaginist of the aryl hydrocarbon
receptor and inhibitor of mitogen-activated protein kinase
kinase. The American Society for Pharmacology and
Experimental Therapeutics. 1998. 53. 438-445.
69. Fan Wang, Debie Hoivik, Richard Pollenz, Stephen Safe,
Functional and physical interactions between the estrogen
receptor sp1 and nuclear aryl hydrocarbon receptor
complexes. Nucleic Acids Research. 1998. 26. 3044-3052.
70. John J. R., Russell C., Patricia M., Suppression of cell
cycle progression by flavonoids:dependence on the aryl
hydrocarbon receptor. Carcinogenesis. 1999. 20. 1561-1566.
71. Shafat A. Quadri, Ariful N. Qadri, Mark E. Hahn, Koren K.
MANN, The bioflavonoid galangin blocks aryl hydrocarbon
receptor activation and polycyclic aromatic hydrocarbon-
induced pre-B cell apoptosis. Mol. Pharmcol. 2000. 58.
515-525.
72. Safe S., Wang F., Porter W., Duan R., McDougal A., Ah
receptor agonists as endocrine disruptors:antiestrogenic
activity and mechanisms. 1998. 101-102. 343-347.
73. Perez EA., Doxorubicin and paclitaxel in the treatment of
advanced breast cancer: efficacy and cardiac
considerations. Cancer Investigation. 2001. 19(2). 155-64.
74. Fricker S.P., Buckley R.G., Comparison of two colorimetric
assays as cytotoxicity endpoints for an in Vitro screen for
antitumour agents. Anticancer Res. 1996. 16. 3755-3760.
75. Papazisis KT., Geromichalos GD., Sivridis E., Tsekreli OK.,
Effects of melatonin on proliferation of cancer cell lines.
J. Pineal. Res. 1998. 25. 211-218.
76. Nip J. Strom DK., Fee BE., Zambetti G., E2F-1 cooperates
with topoisomerase II inhibition and DNA damage to
selectivity augment p53-independent apoptosis.
Molecular & Cellular Biology. 1997. 17(3). 1049-1056.
77. Bertrand R., Solary E., Jenkins J., Pommier Y., Apoptosis
and its modulation in human promyelocytic HL-60 cells with
DNA topoisomerase I and II inhibitors.Blood. 1993. 81. 1359-
1368.
78. Pommier Y., Kohlhagen G., Kohn KW., Leteurtre F., Wani MC.,
Wall ME., interaction of an alkylating camptothecin
derivative with a DNA base at topoisomerase I-DNA cleavage
sites. Proceedings of the National Academy of Sciences of
the nited States of America. 1995. 92. 8861-8865.
79. Solary E., Jenkins J., S Zambetti G., train-specific
differences in formation of apoptotic DNA ladders in MCF-7
breast cancer cells. Cancer Letter. 1999. 144.31-37.
80. Rago R., Mitchen J., Wilding G., DNA fluorometric assay in
96-well tissue culture plates using Hoechst 33258 after
cell lysis by freezing in distilled water. Analytical
Biochemistry. 1990. 191. 31-34.
81. Molina J., Castilla JA., Gil T., Hortas ML. Vergara F.,
Herruzo A., Influence of incubation on the chromatin
condensation and nuclear stability of human spermatozoa by
flow cytometry. Human Reproduction. 1995. 10. 1280-1286.
82. Guillermo E., Pedro F.-S., Sheikh M.-S., Kyung S. L.,
Altered cell cycle control at the G2/M phases in aryl
hydrocarbon receptor-null embryo fibroblast. The American
Society for Pharmacology and Experimental Therapeutics.
2000. 57. 1056-1063.
83. Daniel W. Nebert, Amy L. Roe, Matthew Z. Dieter, Willy A.
Solis, Yi Yang and Timothy P. Dalton, Role of the Aromatic
Hydrocarbon Receptor and [Ah] Gene Battery in the Oxidative
Stress Response,Cell Cycle Control, and Apoptosis. Bioch.
Pharmacol. 2000. 59. 65-85.
84. Xu l., Imawati. B., Hua Z., Xiaodong W., Bid, a bcl2
interacting protein, mediates cytochrome c elease from
mitochondria in response to activation of cell surface
death receptor. Cell. 1998. 94. 481-490.
85. Sebastian Wesselborg, Ingo H. Engels, Evi Rossmann, Marek
Los, and Klaus Schulze-Osthoff, Anticancer Drugs Induce
Caspase-8/FLICE Activation and Apoptosis in the Absence of
CD95 Receptor/Ligand Interaction. The American
Society of Hematology. 1999. 93. 3053-3063.
86. Caricchio, R., Reap, E.A., Cohen, P.L., Fas/Fas ligand
interactions are involved in ultraviolet-B-induced human
lymphocyte apoptosis. Journal of Immunology 1998. 161. 241-
251.
87. Mann K. K., Matulka. R. A., Hahn M. E., Sherr D. H.,
Kerkvliet N. I., The role of polycyclic aromatic
gydrocarbon metabolism in dimethylbenz[a]anthracene-
induced pre-b lymphocyte apoptosis. Toxicol. App.
Pharmacol. 1999. 161. 10-22.
88. Yi-Zhong Gu, John B. Hogenesch, and Christopher A.
Bradfield, THE PAS SUPERFAMILY: Sensors of Environmental
and Developmental Signals. Annu. Rev. Pharmacol. Toxicol.
2000. 40. 519—61.
89. Estrogen and aryl hydrocarbon receptor expression and
crosstalk in human Ishikawa endometrial cancer cells.
J.Ssteroid Bioch. Mol. Bio. 2000. 72. 197-207.
90. Mark W., Matthew S., Brad S., Stephen S., Crosstalk between
estrogen receptor α and aryl hydrocarbon receptor in
breast cancer cells involves unidirectional activation of
proteasomes. FEBS. 2000. 478. 109 -112.
91. Kathleen F. Arcaro., Patrick W., Yi Yang., William Clayton,
Antiestrogenicity of environmental polycyclic aromatic
hydrocarbons in human breast cancer cells. Toxicology.
1999. 133. 115-127.