2-5-dimethylcelecoxib and Glioma

Celecoxib (Celebrex) appears to be unique among the class of selective COX-2 inhibitors (coxibs), because this particular compound exerts a second function that is independent of its celebrated ability to inhibit COX-2. This second function is the potential to inhibit cell proliferation and stimulate apoptotic cell death at much lower concentrations than any other coxibs. Intriguingly, these two functions are mediated by different moieties of the celecoxib molecule and can be separated. The author, as well as others, have generated and investigated analogs of celecoxib that retain only one of these two functions. One derivative, 2,5-dimethyl-celecoxib (DMC), which retains the antiproliferative and apoptosis-inducing function, but completely lacks the COX-2 inhibitory activity, is able to mimic faithfully all of the numerous antitumor effects of celecoxib that have been investigated so far, including reduction of neovascularization and inhibition of experimental tumor growth in various in vivo tumor models. In view of the controversy that has recently arisen regarding the life-threatening side effects of this class of coxibs, it may be worthwhile to pursue further the potential benefits of drugs such as DMC for anticancer therapy. Because DMC is not a coxib yet potently maintains celecoxib's antitumor potential, one may be inclined to speculate that this novel compound could potentially be advantageous in the management of COX-2-independent cancers. In this summary, the implications of recent findings with DMC will be presented and discussed.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Brain Neoplasms; Cyclooxygenase 2; Glioma; Growth Inhibitors; Humans; Pyrazoles; Sulfonamides

Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer. However, when used orally significant gastrointestinal side effects and lack of overall efficacy were documented. Recently, in a phase II trial in Brazil for the treatment of temozolomide (TMZ)-resistant malignant gliomas, POH was well tolerated when administered intranasally. The present study explores the effects and mechanisms of POH on TMZ-sensitive and TMZ-resistant glioma cells. In vitro studies showed that POH was cytotoxic to TMZ-resistant as well as TMZ-sensitive glioma cells, and this effect was independent of O(6)-methylguanine-DNA methyltransferase expression. POH induced cytotoxicity, in part, through the endoplasmic reticulum (ER) stress pathway as shown by the increased expression of glucose-regulated protein-78 (GRP78), activating transcription factor 3, and C/EBP-homologous protein. In addition, POH impeded survival pathways, such as mTOR and Ras. As well, POH reduced the invasive capacity of sensitive and resistant glioma cells. POH alone and/or in combination with other ER stress-inducing cytotoxic drugs (i.e., 2, 5-dimethyl-celecoxib, nelfinavir) further induced apoptosis in TMZ-sensitive and TMZ-resistant glioma cells. To show whether intranasal delivery of POH was effective for the treatment of TMZ-resistant gliomas, animals bearing intracranial tumors were given POH intranasally. Animals treated through intranasal administration of POH exhibited a decrease in tumor growth and an increase in survival. Our data show that POH is an effective anti-glioma cytotoxic agent for TMZ-resistant gliomas when administered intranasally.

Topics: Administration, Intranasal; Animals; Brain Neoplasms; Cell Death; Cell Line, Tumor; Cell Proliferation; Cytokines; Dacarbazine; Drug Resistance, Neoplasm; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Glioma; Humans; Mice; Monoterpenes; Nelfinavir; Neoplasm Invasiveness; Neovascularization, Pathologic; Pyrazoles; Sulfonamides; Temozolomide; Xenograft Model Antitumor Assays

Our laboratory has previously shown that a novel compound, 2,5-dimethyl-celecoxib (DMC), which is structurally similar to the cyclooxygenase-2 (COX-2) inhibitor celecoxib but lacks the COX-2-inhibitory function, mimics the antitumor effects of celecoxib. Most studies on DMC, however, focused on its effects on tumor cells. Here, we investigated the activities of DMC as an antiangiogenic agent in both in vitro and in vivo systems. Using primary cultures of human glioma specimens, we found that DMC treatment was cytotoxic to tumor-associated brain endothelial cells (TuBEC), which was mediated through the endoplasmic reticulum stress pathway. In contrast, confluent cultures of quiescent human BEC did not undergo cell death. DMC potently suppressed the proliferation and migration of the TuBEC. DMC caused no apparent effects on the secretion of vascular endothelial growth factor and interleukin-8 but inhibited the secretion of endothelin-1 in tumor-associated EC. DMC treatment of glioma xenografts in mice resulted in smaller tumors with a pronounced reduction in microvessel density compared with untreated mice. In vitro and in vivo analyses confirmed that DMC has antivascular activity. Considering that DMC targets both tumor cells and tumor-associated ECs, this agent is a promising anticancer drug.

Topics: Angiogenesis Inhibitors; Animals; Brain Neoplasms; Cell Proliferation; Endothelial Cells; Glioma; Humans; Inhibitory Concentration 50; Male; Mice; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Pyrazoles; Sulfonamides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays