[Show abstract][Hide abstract] ABSTRACT: Angiogenesis is an important process in cell development, especially in cancer. Vascular endothelial growth factor (VEGF) signaling is an important regulator of angiogenesis. Several therapies that act against VEGF signal transduction have been developed, including YN968D1, which is a potent inhibitor of the VEGF signaling pathway. This study investigated the antitumor activity of YN968D1 (apatinib mesylate) in vitro and in vivo. YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. YN968D1 effectively inhibited proliferation, migration and tube formation of human umbilical vein endothelial cells induced by FBS, and blocked the budding of rat aortic ring. In vivo, YN968D1 alone and in combination with chemotherapeutic agents effectively inhibited the growth of several established human tumor xenograft models with little toxicity. A phase I study of YN968D1 has shown encouraging antitumor activity and a manageable toxicity profile. These findings suggest that YN968D1 has promise as an antitumor drug and might have clinical benefits.
[Show abstract][Hide abstract] ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
No preview · Article · Oct 2010 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: An unexpected and unusual dimeric platinum(II) tetracarboxylate complex was obtained by the reaction of cis-[Pt(NH(3))(2)I(2)] with disilver dicarboxylate. The complex exhibits greater in vitro anticancer activity and lower toxicity in mice than its parent compound, carboplatin, and is therefore worthy of further evaluation as a potential antitumor dinuclear platinum agent.
No preview · Article · Jul 2010 · Inorganic Chemistry
[Show abstract][Hide abstract] ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
[Show abstract][Hide abstract] ABSTRACT: A series of 7-cycloalkylcamptothecin derivatives were synthesized from camptothecin with two methods. Their biological activities in vitro were evaluated with sulforhodamine-B (SRB) method on four types of human tumor cell lines A549/ATCC, HT29, NCI-H460 and HL60. Most of these camptothecin analogues show higher antitumor activity than the reference compounds SN-38 and Topotecan, with the IC(50) values low to nM level. Structure-activity relationship studies of these compounds mostly match the conclusion we achieved before from quantitative structure-activity relationship (QSAR) research.
[Show abstract][Hide abstract] ABSTRACT: Phytochemical investigation of the stems of Cucumis melo led to the isolation and identification of 21 cucurbitane-type triterpenoids, including nine new compounds (1-9) and 12 known compounds. Their structures were determined on the basis of spectroscopic analyses, chemical methods, and comparison with spectroscopic data in the literature. Two known compounds, cucurbitacin B (10) and cucurbitacin A (11), showed significant cytotoxic activity against the proliferation of A549/ATCC and BEL7402 cells in vitro. Of the new compounds, only compound 7 was weakly cytotoxic. The inhibitory effects of all compounds on the Jak-Stat3 signaling pathway were evaluated, but only cucurbitacin B (10) showed significant inhibitory activity of phosphotyrosine STAT3.
No preview · Article · May 2009 · Journal of Natural Products
[Show abstract][Hide abstract] ABSTRACT: Combretastatin A4 (CA4) is a novel vascular-disrupting agent that has shown promising anticancer effects through its inhibition of microtubule assembly and subsequent disruption of tumor blood flow. In this report, we demonstrate that 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126), a selective inhibitor of mitogen-activated protein kinase kinase (MEK), significantly enhances the cytotoxicity of CA4 in BEL-7402 cells, independently of MEK inhibition. This independence is evidenced by the fact that another, more specific MEK inhibitor, PD0325901 [N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-[2-fluoro-4-iodo-phenylamino]-benzamide], does not have the same effect as U0126. The disassembled microtubules are able to reassemble in the later stages of CA4 treatment, because of the inactivating glucuronidation of CA4. U0126, but not PD0325901, inhibits CA4 glucuronidation, thereby blocking microtubule reassembly and enhancing CA4-induced G(2)/M cell-cycle arrest. Consistent with this, U0126 significantly enhances CA4-induced cytotoxicity for cells in which CA4 glucuronidation occurs, but not for cells in which such glucuronidation does not occur. These results suggest that great caution should be exercised when interpreting data obtained using U0126 or when CA4 is combined with inhibitors of glucuronidation in clinical practice. It is most important to note that these findings indicate that the combination of CA4 with inhibitors of glucuronidation may be a novel and rational strategy for cancer therapy.
Preview · Article · May 2009 · Journal of Pharmacology and Experimental Therapeutics
[Show abstract][Hide abstract] ABSTRACT: A series of E-ring gamma-lactone camptothecin derivatives were synthesized by semi-synthesis via a three-step domino reaction. Their biological activity was evaluated on two types of human tumor cell lines A549 and HT-29 with sulforhodamine-B (SRB) method. The antitumor activity of these compounds was lower than SN-38, only compound 12c was found to be close to the activity of Topotecan. The structure-activity relationship (SAR) of these analogs was studied and discussed.
No preview · Article · Jan 2009 · Bioorganic & medicinal chemistry letters
[Show abstract][Hide abstract] ABSTRACT: A series of novel platinum(II) complexes involving a carrier with HO- peripheral functional group, 2-hydroxy-1,3-propanediamine (HO-pda), cis-[Pt(HO-dpa)X(2)] (X(2)=2Cl(-) (1), C(2)O(4)(2-) (2), malonate (3), 1,1-cyclobutane dicarboxylate (CBDCA) (4), 3-hydroxy-1,1-cyclobutanedicarboxylate (HO-CBDCA) (5)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X-ray diffraction for three representative complexes 1, 4 and 5. The Pt(II) is in a square planar environment and is coordinated in cis position by a chelating HO-pda and 2Cl(-) for 1 and CBDCA for 4 and 5. Pt-N, Pt-Cl and Pt-O distances and coordinate bond angles of N-Pt-N, Cl-Pt-Cl and O-Pt-O are in the normal range. There are two independent molecules in the asymmetric unit of 5, held together by intermolecular hydrogen bonded chain. All the complexes show significant cytotoxicity on the sensitive cell lines SGC-7901, LNcap and A549, and are more active than carboplatin. 4 is also found to be active against the resistant cell A549/ATCC, which suggests that it has less cross-resistance with cisplatin than carboplatin. Moreover 4 shows much greater inhibition of tumor growth than carboplatin in S180-bearing mice, and is therefore worthy of further development as a potential anti-tumor platinum drug.
No preview · Article · Nov 2008 · Journal of inorganic biochemistry
[Show abstract][Hide abstract] ABSTRACT: Bioassay-guided fractionation of the crude extract of Elaeocarpus hainanensis (Elaeocarpaceae), using the proliferation of non-small cell lung cancer A549/ATCC and human hepatocellular carcinoma BEL-7402 cells as a monitor, led to the isolation of ten cucurbitane-type triterpenoids, including three new compounds (1-3) and seven known compounds (4-10). Their structures were determined on the basis of spectroscopic analyses, chemical methods, and comparison with spectroscopic data in literature. The two known compounds, cucurbitacins D (5) and I (10) were found to exhibit the strongest cytotoxicity against A549/ATCC and BEL-7402 cells in vitro with IC50 values of less than 1 microM.
[Show abstract][Hide abstract] ABSTRACT: A series of novel 2,4,5-substituted pyrimidine derivatives were synthesized and evaluated for inhibition against the human hepatocellular carcinoma BEL-7402 cancer cell line. Several compounds showed potent inhibition with an IC(50) value less than 0.10 microM. Structure-activity relationships for this class of compounds at the 2- and 5-position of the pyrimidine scaffold have been elucidated. The most active compound 7gc showed good inhibition of several different human cancer cell lines with IC(50) values from 0.024 to 0.55 microM.
[Show abstract][Hide abstract] ABSTRACT: P-glycoprotein (P-gp) pumps multiple types of drugs out of the cell, using energy generated from ATP, and confers multidrug resistance (MDR) on cancer cells. ZD6474 is an orally active, selective inhibitor of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinases. This study was designed to examine whether ZD6474 reverses P-gp-mediated MDR in cancer cells. Here, we show that clinically achievable levels of ZD6474 reverse P-gp-mediated MDR of the P-gp-overexpressing cell lines derived from breast cancer, MCF-7/adriamycin (ADR), and human oral epidermoid carcinoma, KBV200 to ADR, docetaxel, and vinorelbine. This ability to reverse the P-gp-mediated resistance is comparable to that of another frequently used reversal agent known as verapamil. ZD6474 itself moderately inhibits the proliferation of both MCF-7 and MCF-7/ADR cells with almost equal activity, but its inhibitory effect is not altered by co-incubation with verapamil, suggesting that ZD6474 may not be a substrate of P-gp. In addition, ZD6474 increases the intracellular accumulation of the P-gp substrate, rhodamine-123, and ADR, by enhancing the uptake and/or decreasing the efflux of these compounds in resistant cells. Further studies show that ZD6474 stimulates ATPase activity in a dose-dependent manner, which is required for the proper function of P-gp. In contrast, ZD6474 does not inhibit the expression level of P-gp. Our results suggest that ZD6474 is capable of reversing MDR in cancer cells by directly inhibiting the function of P-gp, a finding that may have clinical implications for ZD6474.
Preview · Article · Nov 2007 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: A series of 3-demethoxycarbonyl-3-carbamate methyl anhydrovinblastine derivatives (compounds 8b-32b) were designed, synthesized, and evaluated for their inhibition activities against human non-small cell lung cancer cell line (A549) and a human cervix epithelial adenocarcinoma cell line (HeLa). The structure-activity relationships of this new series are described in this paper. Cytotoxicity data revealed that the size of substituents and substitution position had important influence on cytotoxic activity. On two cell lines, compounds (8b and 30b) had more potent cytotoxic activity than the lead compound (1e, AVLB). The preliminary antitumor studies of 8b in vivo showed that it might be promising for the development of new antitumor agents.
[Show abstract][Hide abstract] ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
[Show abstract][Hide abstract] ABSTRACT: Combretastatin A4 (CA4) is a novel vascular disrupting agent that has promising clinical efficacy because of its ability to inhibit microtubule assembly and subsequently disrupt tumor blood flow. In this study, we demonstrate that mitogen-activated protein kinases (MAPKs) are critically involved in the cytotoxicity of CA4. CA4 stimulates both extracellular signal-regulated kinases (ERK1/2) and p38 MAPK in the BEL-7402 hepatocellular carcinoma cell line in a time- and dose-dependent manner. This stimulation is a result of CA4-induced microtubule disassembly, which is a reversible process. Reversibility of microtubule disassembly is evidenced by the ability of disassembled microtubules to reassemble just a few hours after CA4 treatment. p38 MAPK, but not ERK1/2, contributes to this microtubule reassembly following CA4 exposure, and only inhibition of p38 MAPK, but not ERK1/2, synergistically enhances CA4-induced G(2)/M cell cycle arrest. Consistent with this, p38 MAPK inhibitors such as SB203580 and SB202190 also synergistically enhance the cytotoxicity of CA4 in cells where p38 MAPK is activated by CA4. This enhancement appears to be specific for CA4 because the cytotoxicity of other microtubule-targeted agents such as paclitaxel, vinorelbine and colchicine was not affected by p38 MAPK inhibitors. These data indicate that p38 MAPK is a potential anticancer target and that the combination of CA4 with p38 MAPK inhibitors may be a novel and promising strategy for cancer therapy.
Preview · Article · Apr 2007 · International Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: The marine natural product scalaradial (SLD) is a potent inhibitor of secretory phospholipase A(2) (sPLA(2)). Our previous work has demonstrated that SLD inhibits epidermal growth factor receptor-mediated Akt phosphorylation, and this effect is independent of sPLA(2). Here we report the role of SLD in extracellular signal-regulated kinase (ERK)1/2 activation. SLD inhibited ERK1/2 phosphorylation within the first 15 min (early inhibition), then stimulated ERK1/2 phosphorylation after 15 min of SLD treatment (late stimulation) in BEL-7402 cells, displaying biphasic regulatory features. Other PLA(2) inhibitors such as the cytosolic and Ca(2+)-independent PLA(2) inhibitor methyl arachidonyl fluorophosphonate, and another sPLA(2) inhibitor, thioetheramide-phosphatidylcholine, only transiently inhibited ERK1/2 phosphorylation and did not display the stimulatory effect. The early inhibition of ERK1/2 phosphorylation by SLD was reversed by the PLA(2) metabolite arachidonic acid, while the late stimulation was abrogated by constitutively active myristolated-Akt. Furthermore, SLD dose- and time-dependently inhibited the phosphorylation of Raf-1 on Ser 259, which is an established event by which Akt inhibits ERK1/2 activation. Taken together, these data demonstrate a biphasic regulation of ERK1/2 phosphorylation by SLD in a time-dependent manner, i.e., early inhibition and late stimulation. The early inhibition of ERK1/2 phosphorylation is mediated by sPLA(2), at least in part, and the late stimulation is effected through SLD inhibition of Akt. These findings provide further insight into the mechanisms underlying the pharmacological effect of SLD.
No preview · Article · Sep 2006 · Cancer biology & therapy