hypericin, which inhibit not only PKC activities 5, 48, 51 but also tyrosine kinase activities of platelet-derived growth factor receptor and epidermal growth factor receptor, 21, 49 respectively, induced apoptotic DNA fragmentation on agarose gel electrophoresis in human glioma cell lines. 16, 17 The present studies were undertaken to use calphostin C, a highly selective PKC inhibitor, 29 and to characterize the relative capacities to promote apoptosis in human glioma cells not only on the basis of the results of agarose gel electrophoresis but also on those of
Hideyasu Ikemoto, Eiichi Tani, Tsuyoshi Matsumoto, Atsuhisa Nakano and Jun-Ichi Furuyama
Ian F. Pollack, Stephanie Kawecki and John S. Lazo
, 35 The effect of UCN-01 on the cell lines examined in this study was initially cytostatic, but with prolonged exposures direct cytotoxicity was apparent. This correlated with the induction of morphological and electrophoretic features of apoptosis (IF Pollack, et al. , unpublished data), a genetically regulated “programmed” form of cell death. Couldwell, et al. , 15 have also noted that PKC inhibition using hypericin induced apoptosis in malignant glioma cell lines. The molecular pathway underlying this effect in cells treated with UCN-01 remains uncertain
H. Bruce Hamilton, David R. Hinton, Ronald E. Law, Rayudu Gopalakrishna, Yu Zhuang Su, Zhen-Hai Chen, Martin H. Weiss and William T. Couldwell
was absent in the noninvasive adenomas analyzed. 3 Hypericin, a conjugated quinone biosynthesized by members of the plant genus Hypericum, is a photodynamic pigment that has been found in vitro to oxidize lipids, amino acids, and proteins and to disrupt the normal function of cellular membranes. 14, 17, 18, 31, 34 Hypericin exhibits antidepressant, antiviral, and (it has been suggested) anti neoplastic properties in some cell types. 5, 6, 10, 20–22, 31, 33 Hypericin has recently been shown to be a potent inhibitor of PKC as well as of other cellular enzymes
Morinaga Shin-Ichiro Nakamura Kaoru Suseki Kazuhisa Takahashi Yoshio Nakajima August 1996 85 2 323 328 10.3171/jns.1996.85.2.0323 Inhibition of cellular growth and induction of apoptosis in pituitary adenoma cell lines by the protein kinase C inhibitor hypericin: potential therapeutic application H. Bruce Hamilton David R. Hinton Ronald E. Law Rayudu Gopalakrishna Yu Zhuang Su Zhen-Hai Chen Martin H. Weiss William T. Couldwell August 1996 85 2 329 334 10.3171/jns.1996.85.2.0329 Thrombin
Michael A. Vogelbaum, Jianxin X. Tong, Ryuji Higashikubo, David H. Gutmann and Keith M. Rich
HB , Hinton DR , Law RE , et al : Inhibition of cellular growth and induction of apoptosis in pituitary adenoma cell lines by the protein kinase C inhibitor hypericin: potential therapeutic application. J Neurosurg 85 : 329 – 334 , 1996 Hamilton HB, Hinton DR, Law RE, et al: Inhibition of cellular growth and induction of apoptosis in pituitary adenoma cell lines by the protein kinase C inhibitor hypericin: potential therapeutic application. J Neurosurg 85: 329–334, 1996 13. Hockenbery DM : bcl-2 in cancer
Christine Wild-Bode, Michael Weller and Wolfgang Wick
: Predicting chemoresistance in human malignant glioma cells: the role of molecular genetic analysis. Int J Cancer 79 : 640 – 644 , 1998 Weller M, Rieger J, Grimmel C, et al: Predicting chemoresistance in human malignant glioma cells: the role of molecular genetic analysis. Int J Cancer 79: 640–644, 1998 22. Weller M , Trepel M , Grimmel C , et al : Hypericin-induced apoptosis of human malignant glioma cells is light-dependent, independent of bcl-2 expression, and does not require wild-type p53. Neurol Res 19
Wei Zhang, Chiedozie Nwagwu, Duc Minh Le, V. Wee Yong, Hua Song and William T. Couldwell
: Inhibition of human malignant glioma cell motility and invasion in vitro by hypericin, a potent protein kinase C inhibitor. Cancer Lett 120 : 31 – 38 , 1997 Zhang W, Law RE, Hinton DR, et al: Inhibition of human malignant glioma cell motility and invasion in vitro by hypericin, a potent protein kinase C inhibitor. Cancer Lett 120: 31–38, 1997 34. Zhu D , Kidder GM , Caveney S , et al : Growth retardation in glioma cells cocultured with cells overexpressing a gap junction protein. Proc Natl Acad Sci USA 89
Vinay Gupta, Yuzhuang S. Su, Weijun Wang, Adel Kardosh, Leonard F. Liebes, Florence M. Hofman, Axel H. Schönthal and Thomas C. Chen
The chemotherapeutic agent temozolomide has demonstrated antitumor activity in patients with recurrent malignant glioma. Because responses are not enduring and recurrence is nearly universal, further improvements are urgently needed.
In an effort to increase the clinical activity of temozolomide, the authors investigated whether its antitumor activity could be enhanced by adding tamoxifen or hypericin, two drugs that are known to inhibit the activity of protein kinase C. Human glioblastoma multiforme cell lines A172 and LA567 were treated with combinations of temozolomide and tamoxifen or hypericin in vitro, and cell survival was analyzed using various methods. Tamoxifen and hypericin were able to greatly increase the growth-inhibitory and apoptosis-stimulatory potency of temozolomide via the downregulation of critical cell cycle–regulatory and prosurvival components. Furthermore, with the use of an in vivo xenograft mouse model, the authors demonstrated that hypericin was able to enhance the antiglioma effects of temozolomide in the in vivo setting as well.
Taken together, analysis of the results indicated that combination therapy involving temozolomide and tamoxifen or hypericin potently inhibited tumor growth by inducing apoptosis and provided an effective means of treating malignant glioma.
cell killing by combination treatment with temozolomide and tamoxifen or hypericin Vinay Gupta M.D. Yuzhuang S. Su M.S. Weijun Wang M.D. Adel Kardosh B.S. Leonard F. Liebes Ph.D. Florence M. Hofman Ph.D. Axel H. Schönthal Ph.D. Thomas C. Chen M.D., Ph.D. 4 2006 20 4 E20 10.3171/foc.2006.20.4.13 FOC.2006.20.4.13 Antitumor properties of dimethyl-celecoxib, a derivative of celecoxib that does not inhibit cyclooxygenase-2: implications for glioma therapy Axel H. Schönthal Ph.D. 4 2006 20 4 E21 10.3171/foc.2006.20.4.14 FOC.2006.20.4.14 Characteristics of tumor