Graphic by CANNABIS CURES CANCERS! (facebook/THeCureForCancers) Photos: Fig. 6. B (Patient 2) Inhibition of the VEGF pathway in two patients with glioblastoma multiforme after cannabinoid treatment. The patients were subjected to Δ9-tetrahydrocannabinol (THC) administration as described in “Materials and Methods.” B: VEGFR-2 activation ... and expression ... in the tumors before and after THC treatment ... Journal of the American Association for Cancer Research August 2004 Abstract Cannabinoids inhibit tumor angiogenesis in mice, but the mechanism of their antiangiogenic action is still unknown. Because the vascular endothelial growth factor (VEGF) pathway plays a critical role in tumor angiogenesis, here we studied whether cannabinoids affect it. ... analysis showed that cannabinoid administration to mice bearing s.c. gliomas lowered the expression of various VEGF pathway-related genes. ... cannabinoids depressed the VEGF pathway by decreasing the production of VEGF ... in cultured glioma cells and in mouse gliomas. ... These changes in the VEGF pathway were paralleled by changes in tumor size. Moreover, intratumoral administration of the cannabinoid Δ9-tetrahydrocannabinol to two patients with glioblastoma multiforme (grade IV astrocytoma) decreased VEGF levels ... in the tumors. Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies. INTRODUCTION To grow beyond minimal size, tumors must generate a new vascular supply for purposes of gas exchange, cell nutrition, and waste disposal. ... They do so by secreting proangiogenic cytokines that promote the formation of blood vessels. Vascular endothelial growth factor (VEGF) ... is considered the most important proangiogenic molecule because it is expressed abundantly by a wide variety of animal and human tumors ... Because overexpression of VEGF ... is causally involved in the progression of many solid tumors, several strategies to inhibit VEGF signaling have been translated into clinical trials in cancer patients ... Cannabinoids, the active components of Cannabis sativa L. (marijuana), and their derivatives exert a wide array of effects ... Marijuana and its derivatives have been used in medicine for many centuries, and there is currently a renaissance in the study of the therapeutic effects of cannabinoids. Today, cannabinoids are approved to palliate the wasting and emesis associated with cancer and AIDS chemotherapy, and ongoing clinical trials are determining whether cannabinoids are effective agents in the treatment of pain, neurodegenerative disorders such as multiple sclerosis, and traumatic brain injury. In addition, cannabinoid administration to mice and/or rats induces the regression of lung adenocarcinomas, gliomas, thyroid epitheliomas, lymphomas, and skin carcinomas. These studies have also evidenced that cannabinoids display a fair drug safety profile and do not produce the generalized cytotoxic effects of conventional chemotherapies, making them potential antitumoral agents. Little is known, however, about the mechanism of cannabinoid antitumoral action in vivo. By modulating key cell signaling pathways, cannabinoids directly induce apoptosis or cell cycle arrest in different transformed cells in vitro. However, the involvement of these events in their antitumoral action in vivo is as yet unknown. More recently ... analyses of the vasculature of gliomas ... and skin carcinomas ... have shown that cannabinoid administration to mice inhibits tumor angiogenesis. These findings prompted us to explore the mechanism by which cannabinoids impair angiogenesis of gliomas and, particularly, the possible impact of cannabinoids on the VEGF pathway. Here, we report that cannabinoid administration inhibits the VEGF pathway in cultured glioma cells, in glioma-bearing mice, and in two patients with glioblastoma multiforme. ... MATERIALS AND METHODS Human Tumor Samples: Tumor biopsies were obtained from two of the patients enrolled in an ongoing Phase I/II clinical trial (at the Neurosurgery Department of Tenerife University Hospital, Spain) aimed at investigating the effect of Δ9-tetrahydrocannabinol administration on the growth of recurrent glioblastoma multiforme. The patients had failed standard therapy, which included surgery, radiotherapy ... and temozolomide chemotherapy (4 cycles). Patients had clear evidence of tumor progression on sequential magnetic resonance scanning before enrollment in the study, had received no anticancer therapy for ∼1 year, and had a fair health status ... Patient 1 (a 48-year-old man) had a right-occipital-lobe tumor (7.5 × 6 cm maximum diameters), and Patient 2 (a 57-year-old-man) had a right-temporal-lobe tumor (6 × 5 cm maximum diameters). Both tumors were diagnosed by the Pathology Department of Tenerife University Hospital as glioblastoma multiforme and showed the hallmarks of this type of tumor (high vascularization, necrotic areas, abundant palisading and mitotic cells, and so on). The tumors were removed extensively by surgery, biopsies were taken, and the tip ... of a silastic infusion cathether ... was placed into the resection cavity. ... Each day 0.5–1.5 (median 1.0) mg of Δ9-tetrahydrocannabinol (100 μg/μl in ethanol solution) were dissolved in 30 ml of physiological saline solution supplemented with 0.5% (w/v) human serum albumin, and the resulting solution was filtered and subsequently administered at a rate of 0.3 ml/min with a syringe pump connected to the s.c. reservoir. Patient 1 started the treatment 4 days after the surgery and received a total amount of 24.5 mg of Δ9-tetrahydrocannabinol for 19 days. The posttreatment biopsy was taken 19 days after the cessation of Δ9-tetrahydrocannabinol administration. Patient 2 started the treatment 4 days after the surgery and received a total amount of 13.5 mg of Δ9-tetrahydrocannabinol for 16 days. The posttreatment biopsy was taken 43 days after the cessation of Δ9-tetrahydrocannabinol administration. ... RESULTS Inhibition of the VEGF Pathway in Two Patients with Glioblastoma Multiforme. To obtain additional support for the potential therapeutic implication of cannabinoid-induced inhibition of the VEGF pathway, we analyzed the tumors of two patients enrolled in a clinical trial aimed at investigating the effect of Δ9-tetrahydrocannabinol, a mixed CB1/CB2 agonist, on recurrent glioblastoma multiforme. The patients were subjected to local Δ9-tetrahydrocannabinol administration, and biopsies were taken before and after the treatment. In both patients, VEGF levels in tumor extracts were lower after cannabinoid inoculation (Fig. 6A). ... DISCUSSION Angiogenesis is a prerequisite for the progression of most solid tumors. In particular, gliomas first acquire their blood supply by co-opting existing normal brain vessels to form a well-vascularized tumor mass without the necessity to initiate angiogenesis. ... When gliomas progress, they become hypoxic as the co-opted vasculature regresses and malignant cells rapidly proliferate. These hypoxic conditions, in turn, induce robust angiogenesis via the VEGF pathway ... and in fact, this angiogenic sprouting distinguishes a grade IV astrocytoma (glioblastoma multiforme) from lower-grade astrocytomas. ... Here, we show that cannabinoid treatment impairs the VEGF pathway in mouse gliomas by blunting VEGF production and signaling. Cannabinoid-induced inhibition of VEGF expression and VEGFR-2 activation also occurred in cultured glioma cells, indicating that the changes observed in vivo may reflect the direct impact of cannabinoids on tumor cells. Moreover, a depression of the VEGF pathway was also evident in two patients with glioblastoma multiforme. Although the changes in VEGFR-2 expression observed in these two patients do not fully mirror the cultured-cell and mouse data, they clearly follow the same direction. ... Recent work has shown that cannabinoids can modulate sphingolipid-metabolizing pathways by increasing the intracellular levels of ceramide, a lipid second messenger that controls cell fate in different systems. ... Moreover, as far as we know, this is also the first report showing that ceramide depresses the VEGF pathway by interfering with VEGF production ... the antiproliferative sphingolipid ceramide would blunt angiogenesis and tumorigenesis ... The use of cannabinoids in medicine is limited by their psychoactive effects ... Although these adverse effects are within the range of those accepted for other medications, especially in cancer treatment, and tend to disappear with tolerance on continuous use, it is obvious that cannabinoid-based therapies devoid of side-effects would be desirable. ... Gliomas are one of the most malignant forms of cancer, resulting in the death of affected patients within 1–2 two years after diagnosis. Current therapies for glioma treatment are usually ineffective or just palliative. Therefore, it is essential to develop new therapeutic strategies for the management of glioblastoma multiforme, which will most likely require a combination of therapies to obtain significant clinical results. In line with the idea that anti-VEGF treatments constitute one of the most promising antitumoral approaches currently available, the present laboratory and clinical findings provide a novel pharmacological target for cannabinoid-based therapies. cancerres.aacrjournals.org/content/64/16/5617.full
Posted on: Thu, 16 Jan 2014 00:57:50 +0000
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