[Abstract unavailable

A series of novel thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde moieties were designed and synthesized. Among them, TSC24 exhibited broad antiproliferative activity in a panel of human tumor cells and suppressed tumor growth in mice. The mechanism research revealed that TSC24 was not only an iron chelator but also a topoisomerase IIalpha catalytic inhibitor. Its inhibition on topoisomerase IIalpha was due to direct interaction with the ATPase domain of topoisomerase IIalpha which led to the block of ATP hydrolysis. Molecular docking predicted that TSC24 might bind at the ATP binding site, which was confirmed by the competitive inhibition assay. These results about the mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity of topoisomerase IIalpha.

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Tetrandrine is an antitumor alkaloid isolated from the root of Stephania tetrandra. We find that micromolar concentrations of tetrandrine irreversibly inhibit the proliferation of human colon carcinoma cells in MTT and clonogenic assays by arresting cells in G 1 . Tetrandrine induces G 1 arrest before the restriction point in nocodazole-and serum-starved synchronized HT29 cells, without affecting the G 1 -S transition in aphidicolin-synchronized cells. Tetrandrine-induced G 1 arrest is followed by apoptosis as shown by fluorescence-activated cell sorting, terminal deoxynucleotidyl transferase-mediated nick end labeling, and annexin V staining assays. Tetrandrine-induced early G 1 arrest is mediated by at least three different mechanisms. First, tetrandrine inhibits purified cyclin-dependent kinase 2 (CDK2)/cyclin E and CDK4 without affecting significantly CDK2/cyclin A, CDK1/cyclin B, and CDK6. Second, tetrandrine induces the proteasome-dependent degradation of CDK4, CDK6, cyclin D1, and E2F1. Third, tetrandrine increases the expression of p53 and p21Cip1 in wild-type p53 HCT116 cells. Collectively, these results show that tetrandrine arrests cells in G 1 by convergent mechanisms, including down-regulation of E2F1 and up-regulation of p53/p21Cip1 .

ABSTRACT:The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα−PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R 1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα−9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors. KEYWORDS: PI3K, PI103, crystal structure, drug design, cancer therapy T he lipid kinase family of phosphatidylinositol 3-kinases (PI3Ks) plays pivotal roles in many cellular processes, including proliferation, survival, differentiation, and metabolism. 1−3 Class I PI3K, the best physiologically, biochemically, and structurally characterized member of the PI3K family, consists of four isoforms, α, β, γ, and δ. Each isoform is a heterodimer that comprises a p110 catalytic subunit and a p85 regulatory subunit. Upon insulin and growth factor stimulation, PI3Ks phosphorylate phosphatidylinositol-3,4-bisphosphate (PIP2) to produce phosphatidylinositol-3,4,5-triphosphate (PIP3). The cellular level of PIP3 is also tightly regulated by phosphatases, such as the phosphatase and tensin homologue (PTEN), which dephosphorylates PIP3 back to PIP2. 4,5 The PI3K pathway is frequently deregulated in a wide range of tumor types as a result of hyperactivation of upstream growth factor signaling, mutation, or loss of PTEN, 6 and oncogenic mutations in PIK3CA, 7 which provides further evidence of the role of PI3K in tumorigenesis. Moreover, accumulating evidence indicates that hyperactivation of PI3Kα is inextricably linked to cancer survival and resistance to existing therapies in a great proportion of human cancers. 8 Therefore, targeting PI3Ks with small-molecular-weight inhibitors provides an attractive opportunity for cancer therapy and for overcoming resistance to current therapies, and thus, significant efforts have recently been made to develop PI3K inhibitors. 9 With multiple ongoing efforts in academic and industrial organizations to develop clinically relevant inhibitors against PI3K, a number of inhibitors have already entered clinical trials. 2,10 PI103 is one of the first synthesized PI3K inhibitors; it belongs to the pyridinylfuranopyrimidine class and inhibits PI3K in an ATP-competitive manner with selectivity toward PI3Kα. 11 PI103 has already demonstrated significant antitumor activity against several human tumor xenografts, especially those with well-established abnormalities in the P...

Dihydroartemisinin (DHA), the main active metabolite of artemisinin derivatives, is one of the most effective anti-malarial analogs of artemisinin. In the current study, we found that DHA inhibited the proliferation of a panel of tumor cells originated from different tissue types. DHA effectively induced apoptosis in human promyelocytic leukemia HL-60 cells, which was accompanied with mitochondrial dysfunction and caspases activation. Further studies indicated that DHA-induced apoptosis was iron-dependent. Though DHA slightly elicited superoxide anion, these reactive oxygen species (ROS) contribute little to DHA-induced apoptosis in HL-60 cells. Moreover, DHA time-dependently activated mitogen-activeted protein kinases (MAPKs) and specific inhibition of p38 MAPK, but not c-Jun-NH2-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK), abolished DHA-induced apoptosis, indicating that activation of p38 MAPK is required for DHA-induced apoptosis in HL-60 cells. Altogether, our data uncover that DHA induces apoptosis is dependent of iron and p38 MAPK activation but not ROS in HL-60 cells.

This study is intended to characterize the cellular target of gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hurburyi tree, which possesses potent in vitro and in vivo antitumor activities. The antiproliferative activity of GA was further confirmed here in a panel of human tumor cells and multidrugresistant cells. We found that GA significantly inhibited the catalytic activity of topoisomerase (Topo) II and, to a comparatively less extent, of Topo I, without trapping and stabilizing covalent topoisomerase-DNA cleavage complexes. Down-regulation of Topo IIA but not Topo I and Topo IIB, reduced GA-induced apoptosis and the phosphorylation of c-Jun, and restored cell proliferation upon GA treatment. Moreover, GA antagonized etoposideinduced DNA damage and abrogated the antiproliferative activity of etoposide, whereas it did not affect camptothecin-induced DNA damage. By dissecting the actions of GA on the individual steps of Topo IIA catalytic cycle, we found that GA inhibited DNA cleavage and ATP hydrolysis. Moreover, GA directly bound to the ATPase domain of Topo IIA, and may share common binding sites with ATP. The results reported here show that GA exerts its antiproliferative effect by inhibiting the catalytic activity Topo IIA. They also indicate that GA inhibits Topo IIA-mediated DNA cleavage and modulate the activity of Topo II poisons, which provide rationale for further clinical evaluation of GA. [Mol Cancer Ther 2007;6(9):2429 -40]

Rapamycin and its analogs (rapalogs) are the first generation of mTOR inhibitors, which have the same molecular scaffold, but different physiochemical properties. Rapalogs are being tested in a wide spectrum of human tumors as both monotherapy and a component of combination therapy. Among them, temsirolimus and everolimus have been approved for the treatment of breast and renal cancer. However, objective response rates with rapalogs in clinical trials are modest and variable. Identification of biomarkers predicting response to rapalogs, and discovery of drug combinations with improved efficacy and tolerated toxicity are critical to moving this class of targeted therapeutics forward. This review focuses on the aberrations in the PI3K/mTOR pathway in human tumor cells or tissues as predictive biomarkers for rapalog efficacy. Recent results of combinational therapy using rapalogs and other anticancer drugs are documented. With the rapid development of next-generation genomic sequencing and precision medicine, rapalogs will provide greater benefits to cancer patients.