A validated in vitro model of cartilage damage and published data were used showing that this model measures the chondroprotective and antiinflammatory effects of different antiarthritic drugs. In this report, this model was used to evaluate the effects of a new antiarthritic Ayurvedic formulation containing Zingiber officinale root, Tinospora cordifolia stem, Phyllanthus emblica fruit and oleoresin of Boswellia serrata. Glucosamine sulphate was used as a positive control in the study. Aqueous extracts of each drug were tested on explant cultures of knee cartilage obtained from osteoarthritis patients undergoing knee replacement surgery. The new formulation caused a sustained and statistically significant inhibition in the release of glycosaminoglycans and aggrecan by cartilage explants from these patients. This formulation also induced a transient antiinflammatory effect as measured by a reduction in the levels of nitric oxide released by explants. Furthermore, the data strongly suggest that oleoresin of B. serrata plays a crucial role in the chondroprotective and antiinflammatory activity of this formulation. In summary, this report provides the first, direct, in vitro biochemical evidence of anti-arthritic activity a new Ayurvedic formulation. This formulation significantly reduced damage of articular knee cartilage from chronic osteoarthritis patients.
Using a validated explant model of in vitro cartilage damage, the effects of aqueous extracts of Withania somnifera (Ashwagandha) root and glucosamine sulphate (GlcS) were tested on the levels of nitric oxide (NO) and glycosaminoglycans (GAGs) secreted by knee cartilage from chronic osteoarthritis (OA) patients. W. somnifera extracts significantly decreased NO release by explants from one subset of patients (antiinflammatory response) and significantly increased levels of NO and GAGs released by explants from the second subset ('non-responders'). This is the first study showing direct, statistically significant, antiinflammatory effects of W. somnifera on human OA cartilage. It also confirmed that glucosamine sulphate exhibited statistically significant, antiinflammatory and chondroprotective activities in human OA cartilage. However, these beneficial effects of GlcS were observed in cartilage explants from 50% of patients tested ('responders'). In contrast, glucosamine significantly increased secretion of NO but not GAGs in explants from the second subset of OA patients ('non-responders'). Cartilage explants from the 11 OA patients gave differential responses to both drugs. Patient samples which responded to the antiinflammatory effects of W. somnifera did not always give a similar response to glucosamine, and vice versa. Thus, this in vitro model of human cartilage damage provides qualitative and statistically significant, quantitative pre-clinical data on antiinflammatory and chondroprotective activities of antiarthritic drugs.
BackgroundLung cancer is the major cause of cancer-related deaths and many cases of Non Small Cell Lung Cancer (NSCLC), a common type of lung cancer, have frequent genetic/oncogenic activation of EGFR, KRAS, PIK3CA, BRAF, and others that drive tumor growth. Some patients though initially respond, but later develop resistance to erlotinib/gefitinib with no option except for cytotoxic therapy. Therefore, development of novel targeted therapeutics is imperative to provide improved survival benefit for NSCLC patients. The mTOR cell survival pathway is activated in naïve, or in response to targeted therapies in NSCLC.MethodsWe have discovered P7170, a small molecule inhibitor of mTORC1/mTORC2/ALK1 and investigated its antitumor efficacy using various in vitro and in vivo models of human NSCLC.ResultsP7170 inhibited the phosphorylation of AKT, S6 and 4EBP1 (substrates for mTORC2 and mTORC1) levels by 80-100% and growth of NSCLC cells. P7170 inhibited anchorage-independent colony formation of NSCLC patient tumor–derived cells subsistent of disease sub-types. The compound also induced apoptosis in NSCLC cell lines. P7170 at a well-tolerated daily dose of 20 mg/kg significantly inhibited the growth of NSCLC xenografts independent of different mutations (EGFR, KRAS, or PIK3CA) or sensitivity to erlotinib. Pharmacokinetic-pharmacodynamic (PK-PD) analysis showed sub-micro molar tumor concentrations along with mTORC1/C2 inhibition.ConclusionsOur results provide evidence of antitumor activity of P7170 in the erlotinib –sensitive and –insensitive models of NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-259) contains supplementary material, which is available to authorized users.
The mTOR pathway is often upregulated in cancer and thus intensively pursued as a target to design novel anticancer therapies. Approved and emerging drugs targeting the mTOR pathway have positively affected the clinical landscape. Recently, activin receptor-like kinase 1 (ALK1), belonging to the TGFb receptor family, has been reported as an emerging target for antiangiogenic cancer therapy. Here, we describe a novel orally efficacious compound, P7170, that inhibits mTORC1/mTORC2/ALK1 activity with a potent cell growth inhibition. In cell-based assays, P7170 strongly inhibited (IC 50 < 10 nmol/L) the phosphorylation of p70S6K (T389) and pAKT (S473). In many cancer cell lines, such as prostate, ovarian, colon, and renal, P7170 treatment resulted in marked cell growth inhibition. Furthermore, it induced G 1 -S cellcycle arrest and autophagy. In vitro HUVEC tube formation, in vivo Matrigel plug, and rat aorta ring assays demonstrated that P7170 exhibited significant antiangiogenic activity. In addition, ALK1 knockdown studies in HUVEC confirmed that the antiangiogenic activity of P7170 was primarily due to ALK1 inhibition. Strong inhibition of ALK1 in addition to mTORC1/mTORC2 differentiates P7170 in its mechanism of action in comparison with existing inhibitors. In vivo mouse xenograft studies revealed P7170 to exhibit a significant dose-dependent tumor growth inhibition in a broad range of human tumor types when administered orally at 10 to 20 mg/kg doses. The distinctive pharmacological profile with favorable pharmacokinetic parameters and in vivo efficacy makes P7170 an attractive candidate for clinical development. It is currently being tested in phase I clinical studies.
The PI3K/mTOR pathway plays an important role in regulating cancer cell proliferation, growth, survival and metabolism. Activation of the PI3K/mTOR pathway by multiple mechanisms is one of the most frequently observed defects in human malignancies. The objective of these studies was to identify a small molecule that has anti-angiogenic activity in addition to PI3K and mTOR activity. P7170, a novel small molecule, inhibits PI3Kα and mTOR enzyme activity with IC50 value of 2.2 nM and 4.4 nM respectively. P7170 also inhibits a number of PI3Kα mutants. The Inhibition of PI3K-mTOR pathway in different cancer cell lines was demonstrated by 80 to 100% inhibition of the expression of phosphorylated AKT (pAKT), S6 ribosomal protein (pS6), and 4EBP1 (p4EBP1) upon treatment with P7170 in a western blot assay. P7170 also inhibited ALK1, an important enzyme involved in angiogenesis, and DNA-PK, an enzyme involved in DNA repair with the IC50 values of 47 and 1.5 nM, respectively. P7170 exhibited potent cytotoxic activity with IC50 values ranging from 2 to 22 nM in a number of cancer cell lines eg. ovarian (A2780), prostate (PC3), triple negative breast (MDA-MB-231 and MDA-MB-468), ER positive breast (MCF7), hepatocellular (HuH-7), renal (786-O), pancreatic (Panc1, AsPC1, and BxPC3), and colon (HCT116, HCT115, SW480) cancer cell lines. More interestingly, P7170 inhibited pAKT and pS6 in stem-like cells isolated from tumor samples of colon, breast, and head and neck cancer patients. P7170 also inhibited anchorage independent colony formation of tumor cells isolated from 39 different human tumor xenografts derived from tumors of patients with different cancers. In addition, P7170 inhibited angiogenesis in vitro in a tube formation assay, and in a matrigel plug assay in animals. It also inhibited metastasis of breast cancer cells. P7170 demonstrated significant in vivo efficacy when administered orally in three human xenograft tumor models. Tumor growth inhibition of 79% at 15 mg/kg in prostate (PC3), 78% at 10 mg/kg in ovarian (A2780), and 64% at 10 mg/kg in triple negative breast (MDA-MB-231) xenografts. Conclusion: P7170 has a unique profile of PI3K-mTOR pathway inhibition along with anti-angiogenic and anti- DNA repair activities. Combined with its effect on stem-like cells, P7170 may prove to be an effective anti-cancer drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3742. doi:1538-7445.AM2012-3742
Major breakthroughs in targeted cancer treatment have been achieved in last decade, but still some patient populations such as Kras mutated non small cell lung cancer (NSCLC), have no therapeutic options other than cytotoxic therapies. Therefore, development of targeted therapeutics is warranted in order to provide improved survival benefit for NSCLC patients with Kras mutation. P7170 is a small molecule inhibitor of PI3K (IC50 = 2.2 nM) and mTOR (IC50 = 4.4 nM). It also inhibits ALK1 and DNA-PK, two important enzymes involved in angiogenesis and DNA repair with IC50 of 47 and 1.5 nM, respectively. The structure, other in vitro, and in vivo efficacy of P7170 has been reported in the accompanying abstract submitted for AACR 2012. P7170 inhibited PI3K-mTOR pathway proteins pAKT, pS6 and p4EBP1 by 90 to 100 % in Kras mutated NSCLC cell line (H460) in a western blot assay. P7170 also exhibited potent cytotoxicity activity against two Kras mutated NSCLC (H460 and A549) cell lines with IC50 values of 7 and 5 nM. P7170 inhibited anchorage independent colony formation of tumor cells isolated from 10 different human tumor xenografts derived from NSCLC patient's tumors (Seven out of 10 samples had wild type Kras, and three had mutations in Kras). Moreover, P7170 induced apoptosis in H460 cell lines by inducing PARP cleavage. More interestingly, P7170 inhibited pAKT and pS6 in a dose dependent fashion in stem-like cells isolated from tumor samples of a Kras mutated NSCLC patient. P7170 demonstrated significant (p<0.01) in vivo efficacy following oral administration, in NSCLC xenograft studies using Kras mutated H460 cancer cell line. P7170 treatment resulted in 66% tumor growth inhibition at a dose of 5 mg/kg, and stabilization of tumor growth (89% tumor growth inhibition) at a dose of 20 mg/kg. Evaluation of mechanism of action of P7170 in H460 xenografted tumors confirmed the inhibition of PI3K-mTOR (pAKT and p4EBP) and Ras-Raf (pERK) pathways. In addition, inhibition of ALK1 and DNA-PK activity with the treatment of P7170 was also confirmed in xenografts. Conclusion: P7170 by virtue of its unique profile represents an opportunity to deliver a first-in-class therapeutic option for patients saddled with Kras mutated non small cell lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3759. doi:1538-7445.AM2012-3759
Hypoxia-inducible factor-1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) are transcription factors and are activated in response to hypoxia. Both HIF-1α and STAT3 regulate various aspects of cancer biology such as cell survival, proliferation, angiogenesis etc. and are constitutively expressed in a wide range of human cancers. In the last decade, over expression of HIF-1α and STAT3 has been demonstrated in many common human cancers, thereby emerging as highly compelling anticancer targets for drug discovery. We herein report the design and synthesis of new imidazopyridine based potent dual inhibitors of HIF-1α and STAT3 pathways. The lead compound of this series P3971 has been identified as a potent inhibitor of HIF-1α (200 nM) and STAT3 (350 nM) with significant antiproliferative activity against various cancer cell lines. Moreover, P3971 was also found to be orally efficacious in HCT116 (colon cancer) and H460 (lung cancer) xenograft mice models.
Triple negative breast cancer (TNBC) lacks ER, PR and Her2 receptor expression & accounts for nearly 10-15% of all breast cancer. It is an aggressive disease with high risk for early relapse & visceral metastasis leading to poor survival as compared to other subtypes. Currently, there is no targeted therapy beyond cytotoxic chemotherapy for TNBC. PI3K-mTOR pathway is often dysregulated (via mutations in PI3K or PTEN) in TNBC and hence offers an opportunity to develop a therapeutic to address the high unmet medical need in this disease. P7170, a small molecule mTOR/PI3K/ALK1 inhibitor with potent antitumor activity in various cancer types {Cancer Res, April 15,2012; 72(8 Supplement): 3742 and 3759} is currently undergoing Phase 1 clinical trial. Here, we report the evaluation of anti-tumor activity and the identification of potential pharmacodynamic markers of P7170 in a TNBC model. P7170 inhibited proliferation (IC50 range 5 - 38 nmol/L) in TNBC cell lines as determined using propidium iodide (PI) assay. In addition, P7170 inhibited anchorage-independent growth of tumor cells isolated from patient derived tumor xenografts evaluated in a clonogenic assay. PI3K-mTOR pathway proteins pS6 and p4EBP1 were potently inhibited whereas pAkt was modestly inhibited by P7170 in MDA-MB-231 cells as assessed by Western blot. It also inhibited migration of MDA-MB-231 cells in a transwell migration assay. P7170 at 1/3rd dose of Maximum tolerated dose (5 mg/kg, po) as a single agent resulted in 63% (P<0.05) tumor growth inhibition in MDA-MB-231 xenograft mouse model. Pharmacodynamic effects of P7170 were evaluated in the plasma, tumor and skin of MDA-MB-231 tumor bearing mice treated with P7170 (5 and 15 mg/kg) orally for 3 days. Expression of target genes was measured by qRT-PCR, tumor and skin proteins were measured by immunohistochemistry, and plasma proteins by ELISA. P7170 significantly reduced pS6 protein in a dose-and time-dependent manner in the tumor and skin. P7170 significantly reduced tumor p4EBP1 protein at the highest dose and reduced tumor CDC25A gene by 2-fold. In addition, P7170 dose-dependently reduced plasma IGF1/IGFBP3 ratios compared to vehicle group. Conclusion: These data suggest that P7170 demonstrates robust antiproliferative activities in vitro and anti-tumor activity in vivo in TNBC. Tumor pS6 protein, CDC25A transcript levels and skin pS6 levels were identified as pharmacodynamic markers of P7170 activity. P7170 could be a therapeutic option for TNBC patients, and warrants testing in a clinical trial. Citation Format: Veena R. Agarwal, Dimple Bhatia, Asavari Joshi, Prabha Mishra, Kalyani G. Bharadwaj, Aurelio S. lobo, Pranoy Menon, Payal Dhar, Prashant Pandey, Sreesha Srinivasa, vinay sonawane. P7170, a novel inhibitor of phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) and activin receptor-like kinase 1 (ALK1) shows anti-tumor activity in triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4521. doi:10.1158/1538-7445.AM2014-4521
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