Enhancement of glioblastoma cell killing by combination treatment with temozolomide and tamoxifen or hypericin

Abstract

Object 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. Methods 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. Conclusions 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.