10'-Fluorovinblastine and 10'-Fluorovincristine: Synthesis of a Key Series of Modified Vinca Alkaloids.
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ABSTRACT:
SUBMITTER: Gotoh H
PROVIDER: S-EPMC3254105 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Malignant melanoma (MM) remains a therapeutic challenge on account of extreme primary resistance to apoptosis and fated acquired chemoresistance. In the current context of molecular classification of MM, the understanding of molecular mechanisms giving rise to these resistances should drive therapeutic choice trough personalized medicine. In order to study mechanisms of MM acquire resistance to VAs, we previously established three VA-resistant cell lines, CAL1R-VCR, CAL1R-VDS, and CAL1R-VRB, by long time exposure of the CAL1-wt MM cell line to IC50 (4nM) of VCR, VDS and VRB respectively. CAL1R-VAs cell lines consisted of polyclonal populations to respect biological diversity of tumour. Then, we searched for determine the resistance process impact on MM cells. We thus performed genome-wide analyses based on comparison of global transcriptomic profile of CAL1R-VAs cells to CAL1-wt. In this way, RNA extracted from each cell line was hybridized to Affimetrix HG-U133 Plus 2.00 GeneChips. After hybridization, microarray data were processed with Robust Multi-array Average (RMA) algorithm. We then performed bioinformatic analyses of microarray data and in vitro investigations in the aim to identify genes and pathways that might predict drug resistance.
2014-09-03 | GSE61007 | GEO
Project description:Malignant melanoma (MM) remains a therapeutic challenge on account of extreme primary resistance to apoptosis and fated acquired chemoresistance. In the current context of molecular classification of MM, the understanding of molecular mechanisms giving rise to these resistances should drive therapeutic choice trough personalized medicine. In order to study mechanisms of MM acquire resistance to VAs, we previously established three VA-resistant cell lines, CAL1R-VCR, CAL1R-VDS, and CAL1R-VRB, by long time exposure of the CAL1-wt MM cell line to IC50 (4nM) of VCR, VDS and VRB respectively. CAL1R-VAs cell lines consisted of polyclonal populations to respect biological diversity of tumour. Then, we searched for determine the resistance process impact on MM cells. We thus performed genome-wide analyses based on comparison of global transcriptomic profile of CAL1R-VAs cells to CAL1-wt. In this way, RNA extracted from each cell line was hybridized to Affimetrix HG-U133 Plus 2.00 GeneChips. After hybridization, microarray data were processed with Robust Multi-array Average (RMA) algorithm. We then performed bioinformatic analyses of microarray data and in vitro investigations in the aim to identify genes and pathways that might predict drug resistance. Melanoma model: CAL1 cell line. Treatments: vinorelbine (VRB), vincristine (VCR), vindesine (VDS). Etablishment of 3 resistant cell lines by long time exposure to vinka-alkaloids (4nM, 6-12 months): CAL1R-VRB, CAL1R-VCR, CAL1R-VDS. RNA extracted from a pooled population of each cell line were hybridized to Affimetrix HG-U133 Plus 2.00 GeneChips. Then, microarray data were processed with Robust Multi-array Average (RMA) algorithm.
2014-09-03 | E-GEOD-61007 | biostudies-arrayexpress
Project description:Malignant melanoma (MM) remains a therapeutic challenge on account of extreme primary resistance to apoptosis and fated acquired chemoresistance. In the current context of molecular classification of MM, the understanding of molecular mechanisms giving rise to these resistances should drive therapeutic choice trough personalized medicine. In order to study mechanisms of MM acquire resistance to VAs, we previously established three VA-resistant cell lines, CAL1R-VCR, CAL1R-VDS, and CAL1R-VRB, by long time exposure of the CAL1-wt MM cell line to IC50 (4nM) of VCR, VDS and VRB respectively. CAL1R-VAs cell lines consisted of polyclonal populations to respect biological diversity of tumour. Then, we searched for determine the resistance process impact on MM cells. We thus performed genome-wide analyses based on comparison of global transcriptomic profile of CAL1R-VAs cells to CAL1-wt. In this way, RNA extracted from each cell line was hybridized to Affimetrix HG-U133 Plus 2.00 GeneChips. After hybridization, microarray data were processed with Robust Multi-array Average (RMA) algorithm. We then performed bioinformatic analyses of microarray data and in vitro investigations in the aim to identify genes and pathways that might predict drug resistance. Melanoma model: CAL1 cell line. Treatments: vinorelbine (VRB), vincristine (VCR), vindesine (VDS). Etablishment of 3 resistant cell lines by long time exposure to vinka-alkaloids (4nM, 6-12 months): CAL1R-VRB, CAL1R-VCR, CAL1R-VDS. RNA extracted from a pooled population of each cell line were hybridized to Affimetrix HG-U133 Plus 2.00 GeneChips. Then, microarray data were processed with Robust Multi-array Average (RMA) algorithm.
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Project description:Three new pyridine type alkaloids, (-)-vinmajpyridines A-C (1-3), along with two known alkaloids, have been isolated from the aerial parts of Vinca major cultivated in Pakistan. Their structures have been elucidated by means of NMR and HRESIMS spectroscopic data. The new alkaloids were evaluated for their cytotoxicity against glioma initiating cell lines (GITC-3# and GITC-18#), glioblastoma cell lines (U-87MG and T98G), and lung cancer cell line A-549, but none of them was active at 20 μg/mL concentration.
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Project description:In polychemotherapy protocols, that is for treatment of neuroblastoma and Ewing sarcoma, Vinca alkaloids and cell cycle-arresting drugs are usually administered on the same day. Here we studied whether this combination enables the optimal antitumour effects of Vinca alkaloids to be manifested.Vinca alkaloids were tested in a preclinical mouse model in vivo and in vitro in combination with cell cycle-arresting drugs. Signalling pathways were characterized using RNA interference.In vitro, knockdown of cyclins significantly inhibited vincristine-induced cell death indicating, in accordance with previous findings, Vinca alkaloids require active cell cycling and M-phase transition for induction of cell death. In contrast, anthracyclines, irradiation and dexamethasone arrested the cell cycle and acted like cytostatic drugs. The combination of Vinca alkaloids with cytostatic therapeutics resulted in diminished cell death in 31 of 36 (86%) tumour cell lines. In a preclinical tumour model, anthracyclines significantly inhibited the antitumour effect of Vinca alkaloids in vivo. Antitumour effects of Vinca alkaloids in the presence of cytostatic drugs were restored by caffeine, which maintained active cell cycling, or by knockdown of p53, which prevented drug-induced cell cycle arrest. Therapeutically most important, optimal antitumour effects were obtained in vivo upon separating the application of Vinca alkaloids from cytostatic therapeutics.Clinical trials are required to prove whether Vinca alkaloids act more efficiently in cancer patients if they are applied uncoupled from cytostatic therapies. On a conceptual level, our data suggest the implementation of polychemotherapy protocols based on molecular mechanisms of drug-drug interactions.This article is commented on by Solary, pp 1555-1557 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12101.
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Project description:This study will evaluate a questionnaire for measuring constipation in children with cancer. The questionnaire used in this study (Constipation Assessment Scale) reliably predicts the presence and severity of constipation in adult patients, but has not been tested in children. The answers to the questionnaire will be used to determine the child’s level of constipation and to plan and provide appropriate care.
Patients up to 21 years of age who are enrolled in National Cancer Institute trials and are taking weekly vinca alkaloids or narcotics twice a day or more may be eligible for this study.
On admission to the study, participants will undergo the following procedures:
* The child (or the child’s parent) will be interviewed about the child’s bowel habits.
* The results of the child’s most recent physical examination related to bowel function will be obtained from the medical record for review.
* A registered dietitian will interview the child or parent about the child’s eating habits.
During the study, participants will undergo the following procedures:
* A registered nurse will interview the child or parent about the child’s bowel movements. This will be done every other day for hospitalized children and three times a week (by phone) for outpatients.
* The child or parent will complete a daily diary of bowel movements.
* A registered dietitian will evaluate the child’s nutritional status periodically (by phone).
Children who are not constipated when they enter the study will receive a stool softener every day to prevent constipation. Children who become constipated during the study will be treated as needed. Patients will be followed for 7 days after the last dose of vinca alkaloid or narcotic for a maximum of 6 weeks.
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Project description:The total synthesis and evaluation of a key systematic series of vinblastines that incorporate the first deep-seated changes to the substituent at C4 are detailed. The synthetic approach features an expanded and redefined scope of a 1,3,4-oxadiazole [4 + 2]/[3 + 2] cycloaddition cascade in which electronically mismatched electron-deficient trisubstituted alkenes and unactivated trisubstituted alkenes were found to productively initiate the cycloaddition cascade with tethered electron-deficient 1,3,4-oxadiazoles. Such cycloaddition cascades were used to directly introduce altered C4 substituents, providing the basis for concise total syntheses of a series of C4 modified vindolines and their subsequent single-step incorporation into the corresponding synthetic vinblastines in routes as short as 8-12 steps. Evaluation of the synthetic vinblastines revealed a surprisingly large impact and role of the C4 substituent on activity even though it was previously not thought to intimately interact with the biological target tubulin. Only the introduction of a C4 methyl ester, a constitutional isomer of vinblastine in which the carbonyl carbon and ester oxygen of the C4 acetate are transposed, provided a synthetic vinblastine that matched the potency of the natural product. In contrast, even introduction of a C4 acetamide or N-methyl carboxamide, which incorporate single heavy atom exchanges (amide NH for ester oxygen) in vinblastine or the C4 methyl ester, provided compounds that were ≥10-fold less active than vinblastine. Other C4 acetate replacements, including a C4 amine, carboxylic acid, hydroxymethyl or acetoxymethyl group, led to even greater reductions in potency. Even replacement of the C4 acetoxy group or its equally active C4 methyl ester with an ethyl or isopropyl ester led to 10-fold or more reductions in activity. These remarkable trends in activity, which correlate with relative tubulin binding affinities, retrospectively may be ascribed to the role the substituent serves as a H-bond acceptor for α-tubulin Lys336 and Asn329 side chains at a site less tolerant of a H-bond donor, placing the methyl group of the C4 acetate or C4 methyl ester in a spatially restricted and well-defined hydrophobic half pocket created by a surrounding well-ordered loop. This remarkable impact of the C4 substituent, its stringency, and even the magnitude of its effect are extraordinary, and indicate that its presence was selected in Nature to enhance the effects of vinblastine and related natural products.
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Project description:Plants are an important source of chemically diverse natural products that target microtubules, one of the most successful targets in cancer therapy. Colchicine, paclitaxel, and vinca alkaloids are the earliest plant-derived microtubule-targeting agents (MTAs), and paclitaxel and vinca alkaloids are currently important drugs used in the treatment of cancer. Several additional plant-derived compounds that act on microtubules with improved anticancer activity are at varying stages of development. Here, we move beyond the well-discussed paclitaxel and vinca alkaloids to present other promising plant-derived MTAs with potential for development as anticancer agents. Various biological and biochemical aspects are discussed. We hope that the review will provide guidance for further exploration and identification of more effective, novel MTAs derived from plant sources.
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Project description:High thymidylate synthase (TS) level in cancer tissue is considered to result in resistance to pemetrexed therapy for advanced stages of nonsquamous non-small cell lung cancers. To further investigate the mechanism of pemetrexed resistance and potential prognostic outcomes in lung cancer, we established pemetrexed-resistant lung adenocarcinoma cell sublines from CL1 harboring a mutated TP53 gene (R248W) and A549 harboring wild-type TP53. We found the TS expression is upregulated in both pemetrexed-resistant sublines and the reduced TS level achieved through shRNA inhibition resulted in higher pemetrexed sensitivity. We also demonstrated that the acquisitions of pemetrexed resistance enhances epithelial-mesenchymal transition (EMT) in vivo with a mice animal model and in vitro with CL1 and A549 sublines, which was associated with upregulation of ZEB1 which, in turn, downregulates E-cadherin and upregulates fibronectin. When ERK1/2 phosphorylation was reduced by an inhibitor (U0126) or siRNA inhibition, both pemetrexed-resistant sublines reduced their migration and invasion abilities. Therefore, the ERK-mediated pathways induce apoptosis with pemetrexed treatment, and may in turn mediate EMT when cancer cells are resistant to pemetrexed. We further demonstrated that the growth of pemetrexed-resistant tumors could be inhibited by vinblastine in vivo and vincristine in vitro. Our data indicate that pemetrexed resistance could be relieved by non-cross-resistant chemotherapeutic drugs such as vinca alkaloids and might be independent to TP53 status. Furthermore, the phosphorylation of ERK was reduced by vincristine. This finding provides a new insight for overcoming pemetrexed resistance and metastasis by application of vinca alkaloids.
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