Anti-cancer effects of selective cannabinoid agonists in pancreatic and breast cancer cells.

OBJECTIVE: Cancer ranks first among the causes of morbidity and mortality all over the world, and it is expected to continue to be the main cause of death in the coming years. Therefore, new molecular targets and therapeutic strategies are urgently needed. In many cases, some reports show increased levels of endocannabinoids and their receptors in cancer, a condition often associated with tumour aggressiveness. Recent studies have suggested that cannabinoid-1/2 receptors contribute to tumour growth in a variety of cancers, including pancreatic, colon, prostate, and breast cancer. Understanding how cannabinoids can regulate key cellular processes involved in tumorigenesis, such as: cell proliferation and cell death, is crucial to improving existing and new therapeutic approaches for the cancer patients. The present study was aimed to characterize the in-vitro effect of L-759633 (a selective CB2 receptor agonist), ACPA (a selective CB1 receptor agonist) and ACEA (a selective CB1 receptor agonist) on the cell proliferation, clonogenicity, and apoptosis in pancreatic (PANC1) and breast (MDA-MB-231) cancer cells. METHODS: The viability and/or proliferation of cells were detected by MTS assay. A clonogenic survival assay was used to detect the ability of a single cell to grow into a colony. Apoptosis was determined with Annexin V staining (Annexin V-FITC/PI test) and by analyzing the expression of Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2). RESULTS: We found that selective CB1/2 agonists suppressed cell proliferation, clonogenicity and induced proapoptotic function in human PANC1 pancreatic and MDA-MB-231 breast cancer cells. Based on our findings, these agonists led to the inhibition of both cell viability and clonogenic growth in a dose dependent manner. CB1/2 agonists were observed to induce intrinsic apoptotic pathway by upregulating Bax, while downregulating Bcl-2 expression levels. CONCLUSION: Our data suggests that CB1/2 agonists have the therapeutic potential through the inhibition of survival of human PANC1 pancreatic and MDA-MB-231 breast cancer cells and also might be linked with further cellular mechanisms for the prevention (Fig. 5, Ref. 49).

Zingerone ameliorates oxidative stress and inflammation in bleomycin-induced pulmonary fibrosis: modulation of the expression of TGF-ß1 and iNOS.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with limited treatment options. Zingerone found in ginger (Zingiber officinale L.) has many pharmacological effects, especially antiinflammatory and antioxidant activity. However, the effect of zingerone on pulmonary fibrosis (PF) is not fully known. The aim of this study was to investigate the effect of zingerone on bleomycin (BLM)-induced PF and its underlying mechanisms. Wistar-albino rats were given single dose of BLM (5 mg/kg, intratracheal) or vehicle (saline). In treatment groups, zingerone (50 and 100 mg/kg, p.o.) was administered orally for 14 days after BLM administration. Rats and lung tissue were weighed to determine lung index. Antioxidant, antiinflammatory effects, and hydroxyproline content of zingerone were determined by ELISA method. Pulmonary inflammation, collagen deposition, and fibrosis score were determined with Hematoxylin-Eosin (HxE) and Masson's trichrome staining. Transforming growth factor-beta 1 (TGF-ß1) and inducible nitric oxide synthase (iNOS) expressions were detected immunohistochemically. BLM administration increased lipid peroxidation (MDA) and decreased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity. In addition, BLM caused increased levels of tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß) in bronchoalveolar lavage fluid (BALF) and accumulation of collagen bundles. Zingerone administration decreased collagen accumulation, TNF-α and IL-1ß levels, MDA level, TGF-ß1, and iNOS expression and increased SOD and GPx activity. Histopathological findings supported the results. These results show that zingerone (50 and 100 mg/kg) at both doses significantly contributes to healing of PF by improving inflammation, oxidative stress, and histopathological alterations and by affecting TGF-ß1 and iNOS signaling pathways.

Histopathological evaluation of the effect of locally administered strontium on healing time in mandibular fractures: An experimental study.

BACKGROUND: Mandibular fractures are the most common facial fractures. They can be treated by conservative techniques or by surgery. The authors hypothesized that the application of a single local dose of strontium chloride would accelerate the healing of subcondylar mandibular fractures, shorten the recovery time and prevent complications. OBJECTIVES: The aim of the present pilot study was to evaluate the effects of a single local dose of strontium chloride on the healing of subcondylar mandibular fractures in rats. MATERIAL AND METHODS: This randomized experimental study was carried out on 24 male Wistar albino rats. The rats were randomly divided into 3 groups: experimental group 1, receiving 3% strontium chloride; experimental group 2, receiving 5% strontium chloride; and the control group. A full thickness surgical osteotomy was created in the subcondylar area. A single dose of strontium solution (0.3 cc/site) was administered locally by injection on the bone surfaces of the fracture line created. Nothing was administered to the control group. The mandibles were dissected on postoperative day 21. The fractured hemimandibles were submitted to histopathological examination. RESULTS: The median bone fracture healing score was 9 (range: 7-9) in experimental group 1; 8 (range: 7-10) in experimental group 2; and 7.50 (range: 7-8) in the control group. When the groups were compared in terms of bone healing scores, there was a statistically significant difference between experimental group 1 and the control group (p < 0.05). CONCLUSIONS: This study is the first to show that local strontium may have positive effects on the healing of subcondylar mandibular fractures. In the authors' opinion, 3% strontium was beneficial for accelerating facial skeleton consolidation and bone regeneration in rat subcondylar mandibular fractures. This treatment procedure may be combined with closed fracture treatment or a conservative approach.

Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells.

In the present study, we investigated the effects of motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed.

Anticancer effect of COX-2 inhibitor DuP-697 alone and in combination with tyrosine kinase inhibitor (E7080) on colon cancer cell lines.

Colorectal cancer remains one of the most common types of cancer and a leading cause of cancer death worldwide. In this study, we aimed to investigate effects of DuP-697, an irreversible selective inhibitor of COX- 2 on colorectal cancer cells alone and in combination with a promising new multi-targeted kinase inhibitor E7080. The HT29 colorectal cancer cell line was used. Real time cell analysis (xCELLigence system) was conducted to determine effects on colorectal cell proliferation, angiogenesis was assessed with a chorioallantoic membrane model and apoptosis was determined with annexin V staining. We found that DuP-697 alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. For the antiproliferative effect the half maximum inhibition concentration (IC50) was 4.28?10-8 mol/L. Antiangiogenic scores were 1.2, 0.8 and 0.5 for 100, 10 and 1 nmol/L DuP-697 concentrations, respectively. We detected apoptosis in 52% of HT29 colorectal cancer cells after administration of 100 nmol/L DuP-697. Also in combination with the thyrosine kinase inhibitor E7080 strong antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells were observed. This study indicates that DuP-697 may be a promising agent in the treatment of colorectal cancer. Additionally the increased effects observed in the combination with thyrosine kinase inhibitor give the possibility to use lower doses of DuP-697 and E7080 which can avoid and/or minimize side effects.

The effect of octreotide, an analog of somatostatin, on bleomycin-induced interstitial pulmonary fibrosis in rats.

In this study, octreotide (OCT), a synthetic somatostatin analog, was tested for its beneficial effects in the prevention of interstitial pulmonary fibrosis (IPF) induced by bleomycin (BLM) in rats by histological examination and by evaluating tissue OH-proline levels. Thirty male Wistar rats were divided randomly into three groups: group I: intratracheal (i.t.) BLM (7.5 mg/kg, single dose) + saline solution [0.9% NaCl, subcutaneously (s.c.), once-daily for 7 days]; group II: i.t. BLM (7.5 mg/kg, single dose) + OCT acetate (82.5 µg/kg, s.c., once-daily for 7 days); and the control group. At the end of the 7 days, lung tissues were excised and examined by histopathological methods. Levels of tissue hydroxyproline (OH-proline) were determined. BLM administration resulted in prominent histopathologic findings, such as diffuse alveolar damage and interstitial pulmonary fibrosis, as well as a significant increase in OH-proline level, as compared to controls. OCT application explicitly attenuated the histopathologic changes to a significant extent. OCT decreased paranchymal fibrosis and structural deformities in BLM-induced lung fibrosis. These results suggest that OCT administration to rats with BLM-induced IPF has a protective effect. Further studies are necessary to reveal the molecular mechanism(s) of OCT-induced protective effect.

The Evaluation of Microcarcinoma in Differentiated Thyroid Cancers According to Old and New TNM Classification.

OBJECTIVE: In this study, we aimed to evaluate the tumor size for proximal and distant metastases when the new and old TNM classification is taken into account in differentiated thyroid cancers. MATERIAL AND METHODS: Two hundred sixty eight patients diagnosed with thyroid carcinoma, undergoing bilateral total or subtotal thyroidectomy treated with high doses of I-131 were examined retrospectively. The data of these patients were compared after classification, according to tumor size <1 cm and <2 cm, lymph node metastases thyroid and tumor capsule invasion at the time of diagnosis, and accumulation of abnormal activity in post I-131 treatment whole-body scan. I-131 uptakes besides physiological and thyroid bed were considered as abnormal activity uptakes. RESULTS: A total of 268 patients with average age of 19-82 yrs (mean: 47.0±13.8 yrs) were included in the study. At postoperative histopathological evaluation, 228 (85.1%) of patients were reported as papillary, 13 (4.9%) as follicular, 23 (8.6%) as well differentiated tumor of unknown malignant potential, 2 (0.7%) as insular and 2 (0.7%) as Hürthle-cell carcinoma. In patients with known tumor size, 96 of 207 (46.4%) patients' tumor size was <1 cm and in 111 (53.6%) >1 cm. In the same group, according to the revised TNM classification, in 149 of 207 patients (72%) the tumor size was <2 cm, whereas in 58 (28%) >2 cm. Of 187 patients with negative lymph nodes, 15 (8%) showed abnormal activity accumulation in the first post I-131 treatment whole-body scan and 10 (40% of 25 patients) positive lymph node (p<0.05) involvement. CONCLUSION: Since the treatment of patients with microcarcinoma is controversial, tumor size should not be the only factor considered in patients with differentiated thyroid cancer Tissue tumor invasion, age, gender and multifocality should also be taken into account. CONFLICT OF INTEREST: None declared.