39 research outputs found
P-glycoprotein and metallothionein expression and resistance to chemotherapy in osteosarcoma.
The expression of the drug resistance (DR) mediators P-glycoprotein (P-gp) and the metallothioneins (MT) was assessed immunohistochemically in biopsy material from patients with high-grade malignant osteosarcoma (OS). No significant difference was found in survival rate between expressors of both P-gp and MT and non-expressors. Thus, it was concluded that lack of expression of these two drug resistance-related proteins does not appear to confer any advantage in terms of patient survival in osteosarcoma
The evaluation of selected ghanaian medicinal plants for cytotoxic activites
Cancer is still responsible for many deaths worldwide. Therefore, the need for an effective management, treatment and cure of cancer is undoubtedly crucial. In Ghana, several plants or herbal products are used by traditional healers for the management and/or the treatment of various cancers. However, the efficacies of these plant products as anticancer agents are often ill defined. In this study, the methanolic extracts of ten plant species were evaluated for cytotoxicity against three human cancer cell lines, DLD-
1, MCF-7 and M14, using the MTT assay. Extracts of Adenia lobata root, Clerodendrum capitatum leaves, Garcinia kola stem bark, Plumbago zeylanica leaves and Vernonia conferta root, showed relatively low cytotoxic activities while extracts of Ficus asperifolia leaves, Paullinia pinnata root and Thonningia sanguinea root exhibited moderate activity (IC50 values 40 – 55μg/ml against at least one of the three cell lines). Croton membranaceus root extract exhibited markedly higher cytotoxic activities,
particularly against the DLD-1 and MCF-7 cells (IC50 = 16.0 and 17.4μg/ml respectively), while Zanthoxylum xanthoxyloides bark extract was 2-3 fold more active against DLD-1 cells (IC50 = 16μg/ml), than against the other cell lines. These results lend some support for the use of these species in traditional medicines for the treatment of cancer, especially for C. membranaceus and Z. xanthoxyloides.Journal of Science & Technology (Ghana) Vol. 27 (2) 2007: pp. 16-2
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Application of small molecule FPR1 antagonists in the treatment of cancers
YesThe formylpeptide receptor-1 (FPR1) is a member of the chemotactic GPCR-7TM formyl peptide receptor family, whose principle function is in trafficking of various leukocytes into sites of bacterial infection and inflammation. More recently, FPR1 has been shown to be expressed in different types of cancer and in this context, plays a significant role in their expansion, resistance and recurrence. ICT12035 is a selective and potent (30 nM in calcium mobilisation assay) small molecule FPR1 antagonist. Here, we demonstrate the efficacy of ICT12035, in a number of 2D and 3D proliferation and invasion in vitro assays and an in vivo model. Our results demonstrate that targeting FPR1 by a selective small molecule antagonist, such as ICT12035, can provide a new avenue for the treatment of cancers
Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo
BACKGROUND: Activating mutations of FGFR3 are frequently identified in superficial urothelial carcinoma (UC) and increased expression of FGFR1 and FGFR3 are common in both superficial and invasive UC. METHODS: The effects of inhibition of receptor activity by three small molecule inhibitors (PD173074, TKI-258 and SU5402) were investigated in a panel of bladder tumour cell lines with known FGFR expression levels and FGFR3 mutation status. RESULTS: All inhibitors prevented activation of FGFR3, and inhibited downstream MAPK pathway signalling. Response was related to FGFR3 and/or FGFR1 expression levels. Cell lines with the highest levels of FGFR expression showed the greatest response and little or no effect was measured in normal human urothelial cells or in UC cell lines with activating RAS gene mutations. In sensitive cell lines, the drugs induced cell cycle arrest and/or apoptosis. IC(50) values for PD173074 and TKI-258 were in the nanomolar concentration range compared with micromolar concentrations for SU5402. PD173074 showed the greatest effects in vitro and in vivo significantly delayed the growth of subcutaneous bladder tumour xenografts. CONCLUSION: These results indicate that inhibition of FGFR1 and wild-type or mutant FGFR3 may represent a useful therapeutic approach in patients with both non-muscle invasive and muscle invasive UC
Study of the chemotactic response of multicellular spheroids in a microfluidic device
YesWe report the first application of a microfluidic device to observe chemotactic migration in
multicellular spheroids. A microfluidic device was designed comprising a central microchamber
and two lateral channels through which reagents can be introduced. Multicellular
spheroids were embedded in collagen and introduced to the microchamber. A gradient of
fetal bovine serum (FBS) was established across the central chamber by addition of growth
media containing serum into one of the lateral channels. We observe that spheroids of oral
squamous carcinoma cells OSC–19 invade collectively in the direction of the gradient of
FBS. This invasion is more directional and aggressive than that observed for individual cells
in the same experimental setup. In contrast to spheroids of OSC–19, U87-MG multicellular
spheroids migrate as individual cells. A study of the exposure of spheroids to the chemoattractant
shows that the rate of diffusion into the spheroid is slow and thus, the chemoattractant
wave engulfs the spheroid before diffusing through it.This work has been supported by National Research Program of Spain (DPI2011-28262-c04-01) and by the project "MICROANGIOTHECAN" (CIBERBBN, IMIBIC and SEOM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Semi-Synthetic Analogues of Cryptolepine as a Potential Source of Sustainable Drugs for the Treatment of Malaria, Human African Trypanosomiasis and Cancer
YesThe prospect of eradicating malaria continues to be challenging in the face of increasing
parasite resistance to antimalarial drugs so that novel antimalarials active against asexual,
sexual, and liver-stage malaria parasites are urgently needed. In addition, new antimalarials
need to be affordable and available to those most in need and, bearing in mind climate
change, should ideally be sustainable. The West African climbing shrub Cryptolepis
sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid,
cryptolepine (1), has been shown to have antimalarial properties, and the synthetic
analogue 2,7-dibromocryptolepine (2) is of interest as a lead toward new antimalarial
agents. Cryptolepine (1) was isolated using a two-step Soxhlet extraction of C.
sanguinolenta roots, followed by crystallization (yield 0.8% calculated as a base with
respect to the dried roots). Semi-synthetic 7-bromo- (3), 7, 9-dibromo- (4), 7-iodo- (5), and
7, 9-dibromocryptolepine (6) were obtained in excellent yields by reaction of 1 with
N-bromo- or N-iodosuccinimide in trifluoroacetic acid as a solvent. All compounds
were active against Plasmodia in vitro, but 6 showed the most selective profile with
respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC50 = 0.25 µM, SI
= 113; late stage, gametocytes, IC50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites
IC50 = 6.13 µM, SI = 4.6. Compounds 3–6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC50 = 0.11 µM). In addition, 3–6 potently
inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the
most selective (IC50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type
ovarian cancer cells as well as adriamycin-resistant and, except for 5, cisplatin-resistant
ovarian cancer cells. In an acute oral toxicity test in mice, 3–6 did not exhibit toxic effects at
doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C.
sanguinolenta may be utilized as a sustainable source of novel compounds that may lead
to the development of novel agents for the treatment of malaria, African trypanosomiasis,
and cancer
PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma
Background
Many urothelial carcinomas (UC) contain activating PIK3CA mutations. In telomerase-immortalized normal urothelial cells (TERT-NHUC), ectopic expression of mutant PIK3CA induces PI3K pathway activation, cell proliferation and cell migration. However, it is not clear whether advanced UC tumors are PIK3CA-dependent and whether PI3K pathway inhibition is a good therapeutic option in such cases.
Methods
We used retrovirus-mediated delivery of shRNA to knock down mutant PIK3CA in UC cell lines and assessed effects on pathway activation, cell proliferation, migration and tumorigenicity. The effect of the class I PI3K inhibitor GDC-0941 was assessed in a panel of UC cell lines with a range of known molecular alterations in the PI3K pathway.
Results
Specific knockdown of PIK3CA inhibited proliferation, migration, anchorage-independent growth and in vivo tumor growth of cells with PIK3CA mutations. Sensitivity to GDC-0941 was dependent on hotspot PIK3CA mutation status. Cells with rare PIK3CA mutations and co-occurring TSC1 or PTEN mutations were less sensitive. Furthermore, downstream PI3K pathway alterations in TSC1 or PTEN or co-occurring AKT1 and RAS gene mutations were associated with GDC-0941 resistance.
Conclusions
Mutant PIK3CA is a potent oncogenic driver in many UC cell lines and may represent a valuable therapeutic target in advanced bladder cancer
Development of a modified hollow fibre assay for studying agents targeting the tumour neovasculature
Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo
Hypoxia is an important factor in tumor growth. It is associated with resistance to conventional anticancer treatments. Gene therapy targeting hypoxic tumor cells therefore has the potential to enhance the efficacy of treatment of solid tumors. Transfection of a panel of tumor cell lines with plasmid constructs containing hypoxia-responsive promoter elements from the genes, vascular endothelial growth factor (VEGF) and erythropoietin, linked to the minimal cytomegalovirus (mCMV) or minimal interleukin-2 (mIL-2) promoters showed optimum hypoxia-inducible luciferase reporter gene expression with five repeats of VEGF hypoxic-response element linked to the mCMV promoter. Adenoviral vectors using this hypoxia-inducible promoter to drive therapeutic transgenes produced hypoxia-specific cell kill of HT1080 and HCT116 cells in the presence of prodrug with both herpes simplex virus thymidine kinase/ganciclovir and nitroreductase (NTR)/CB1954 prodrug-activating systems. Significant cytotoxic effects were also observed in patient-derived human ovarian cancer cells. The NTR/CB1954 system provided more readily controllable transgene expression and so was used for in vivo experiments of human HCT116 xenografts in nude mice. Subjects treated intratumorally with Ad-VEGFmCMV-NTR and intraperitoneal injection of CB1954 demonstrated a statistically significant reduction in tumor growth. Immunohistochemistry of treated xenografts showed a good correlation between transgene expression and hypoxic areas. Further investigation of these hypoxia-inducible adenoviral vectors, alone or in combination with existing modalities of cancer therapy, may aid in the future development of successful Gene-Directed Enzyme Prodrug Therapy systems, which are much needed for targeting solid tumors