Molecules For Cancer Therapy Research Articles

Small Molecules in Cancer Therapy: Cytotoxics and Molecularly Targeted Agents

Treating different cancers is a major challenge nowadays. Several molecules on the cell surface, in the cell particles and genes, can be targets to inhibit the growth of cancerous cells or to stop metastatic processes. Different small molecules are in the focus of newly targeted therapy areas. Cytoplasmatic skeleton structure as well as apparently expressed mitotic regulators can be targets in tumour therapy. Angiogenesis is essential for tumor growth and spreading, therefore NAD(P)H oxidase can also be a target. Ras/Raf/MEK/MAPK pathway can affect multiple cellular functions by stimulating tumor growth. ICMT methylation of prenylated proteins is important for the correct localization and function of a number of proteins ending in cysteine aliphatic residue, therefore ICMT is an enzyme target in anticancer drug discovery. The abnormal activations of several growth factor receptors and their signaling pathways have been implicated in the development and progression of cancerous processes. Activation of JAK/STAT signaling rout occurs with high frequency in humans. The increased activity of STAT in cancerous tissues enhances the level of Bcl-xL and hereby contributes to the drug resistance in chemotherapy. Therefore tyrosine kinase activity can be a therapeutic target as well. Hsp90 participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis and metastasis. The inhibitions of histone deacetylase in recent years have an important part of targeted therapy as well. Also selective inhibition of NF-κB signaling is possible in cancer therapy. This review would give an account of the action mechanism of current small molecules and newly developed ones in experimental phase in cancer therapy. The effectiveness of these molecules and their combination with each other and their combination with other therapies will be discussed. Keywords: Cancer therapy, small molecules, signal transduction, redox homeostasis, L-carnitine, adenosine/homocysteine, colchicine, Vinca alcaloids, autumnale, ZD6126, N-acetylcolchinol, IB kinase, vinblastine, glucocorticoids, ubiquitinate, cyclooxygenase 2, GADD45, bcl-2, c-myc, patupilone, epothilone B, EPO906, myxobacterium Sorangium - cellulosum, Taxus vifolia, Taxus brevifolia, fluorouracil, Epothilones, 2-phenylindole-3-carbaldehydes, anthracenones, benzophenones, xklp2, BRCA1, Ajuba, TACC, kinetochores, docetaxel, paclitaxel, ixabepilone, epothilone D, ZK EPO, Epigallocatechin, –, 3-gallate, MEK, MAPK, farnesyltransferase, geranylgeranyl transferases (GGTase), isoprenylcysteine carboxyl methyltransferase (ICMT), Cysmethynil, lonafarnib, Sorafenib, butein, quinazolines, gefitinib, erlotinib, imatinib mesylate, indolinones, SU5614, SU5616, SU6561, SU6597, SU6663, SU6668, SU11248, SU4984, SU5402, geldanamycin, herbimycin, radicicol, deguelin, derrubone, macbecin

It is not necessarily YY1—the frequently forgotten Yin-Yang-2 transcription factor

de Nigris et al. (1) performed an interesting study on the functional implication of YY1 in the VEGF regulatory network, leading to a rationale for using YY1 as a therapeutic target molecule in cancer therapy. However, considering the application of YY1 for antiangiogenic treatment bears a fundamental risk because the observed effects are not necessarily specific for YY1: the YY1 antibody (C-20, sc-281, Santa Cruz Biotechnology) used for (chromatin-) immunoprecipitation experiments and Western blotting does not detect exclusively YY1 but also the highly homologous YY2 transcription factor, as previously shown (2). Notably, increasing evidence is given that YY2 is regulated specifically and independently of YY1 (3), and, if both factors are expressed within a particular cell, they can compete for the same regulatory element, frequently mediating antagonistic transcriptional effects (2, 4). Because YY2 is evolved from a retroposition event of the YY1 gene (5), the second technical concern is a matter of the (commercial) siRNA against YY1. The exact sequence has not been provided by the authors (or in the literature they refer to) so that cross-specificity on YY2 RNA cannot yet be excluded. Before a final conclusion that YY1 represents a crucial molecular target for antiangiogenic therapy in cancer, confirmatory experiments on the specific effects of YY1 are required. However, we agree with de Nigris et al. that Yin-Yang transcription factors deserve highest interest regarding their implication in cancer biology.

Abstract A24: High expression of ErbB2 contributes to cholangiocarcinoma cell invasion and proliferation through AKT/p70S6K

Abstract Cholangiocarcinoma (CCA), an adenocarcinoma of the biliary tract, is an incurable and highly lethal cancer. Its incidence has been increasing worldwide during to the past three decades and all cases have almost the same mortality rate. Due to the lack of a specific tumor marker and its silent symptom, this tumor is difficult to diagnose and the majority of patients present at the late stage (stage III or IV) of the disease progression. From 70% to 80% of CCA patients are inoperable and are generally treated by chemotherapy and radiation, which unfortunately have no significant impact for long-term survival. Thus, new diagnostic/prognosis markers and targeted therapies for CCA need to be investigated. Several lines of evidences have implicated the role of ErbB2 in aggressive forms of CCA. High expression of ErbB2 has been found in a variety of non-cancerous biliary proliferative diseases, such as in hepatolithiasis and primary sclerosing cholangitis, both of which are risk factors associated with CCA. Immunohistochemical data have demonstrated that 20% to 30% of tumor specimens from CCA patients show moderate to strong immunostaining for ErbB2 and most of them confer poor clinical outcomes (high metastasis and short survival rate). Moreover, about 30% of transgenic mice constitutively expressing wide type Neu develop gallbladder cancer and intrahepatic CCA within 8 months. Although many reports have indicated the involvement of ErbB2 in cholangiocarcinogenesis and CCA progression, the mechanism of aberrant ErbB2 expression in promoting CCA progression remains unclear. In this study, the role of ErbB2 in governing the malignant phenotype (invasion and proliferation) of CCA was investigated by suppressing ErbB2 function in three human CCA cell lines expressing different levels of ErbB2. Level of endogenous ErbB2 expression in three CCA cell lines, namely HuCCA-1, KKU-100 and KKU-M213, was determined by real time RT-PCR. Two ErbB2 inhibitory methods, a small molecule ErbB2 kinase inhibitor (AG825) and siRNA, were used to disrupt ErbB2 function in the cell lines. CCA cell invasion, motility and proliferation under ErbB2-disrupted conditions were detected using Transwell and MTT assays. In addition, ErbB2 downstream effectors were investigated by western blot analysis. Suppression of ErbB2 activity using a specific kinase inhibitor (AG825) reduced invasion, motility, and proliferation of all three CCA cell lines. The ability of this drug to inhibit neoplastic properties (invasion, motility and proliferation) increased concomitantly with the level of ErbB2 expression. Similarly, knockdown of ErbB2 level by siRNA inhibited cell invasion and proliferation of KKU-M213, a high ErbB2-expressing cell, better than those of the lower ErbB2-expressing cells, HuCCA-1 and KKU-100. Thus, both inhibitory methods indicated that there is more ErbB2-dependency for malignancy of high ErbB2-expressing cell, KKU-M213, than that of low ErbB2-expressing ones. In addition, interrupting ErbB2 activity decreased phosphorylation of AKT and p70S6K, but not ERK1/2, in the high ErbB2 expressing CCA cell line. Our data indicated that high ErbB2 expression enhances CCA invasion, motility and proliferation via AKT/p70S6K pathway, indicating the possibility of targeting these molecules for cancer therapy. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A24.

Abstract 3928: KU-0060019, a novel small molecule inhibitor of ATM

Abstract Ataxia telangiectasia mutated (ATM) is an important serine/threonine kinase involved in the DNA damage response and cell cycle checkpoint control. The 350kDa protein is a member of the PI3-kinase like kinase (PIKK) family and is mutated in the neurodegenerative disorder, Ataxia telangiectasia. ATM exists in the inactive form as a dimer but following DNA damage is phosphorylated at a serine residue at position 1981 and dissociates to become an active monomer. It detects DNA double strand breaks (DSBs) through the Mre11/Rad50/NBS1 (MRN) complex and signals this information downstream to the cell cycle machinery, for example by the phosphorylation of p53 (Ser15) and Chk2 (Thr68). ATM is a key signalling molecule for DNA double strand breaks that can regulate the homologous recombination repair pathway. Inhibition of ATM activity sensitises cells to the cytotoxic effects of DNA damaging agents such as some chemotherapies or ionising radiation that either directly or indirectly induce double stand breaks. Here we present the biological profile of KU-0060019, a potent and specific novel small molecule inhibitor of ATM kinase activity. The compound has an IC50 value against the enzyme of 5 nM with above 1 μM IC50 value against DNA-PK and inhibits cellular phosphorylation of p53 at serine 15 with an EC50 value of 150 nM. It sensitises cells to chemotherapeutics, in particular topoisomerase II inhibitors, as well as radiotherapeutics in vitro in a variety of cancer cell lines. We also demonstrate potentiation of chemotherapeutics in in vivo mouse xenograft tumour models. Using the novel ATM inhibitor KU-0060019 these studies demonstrate the potential of targeting ATM as a sensitising mechanism by a small molecule in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3928.

Oligomannurarate sulfate blocks tumor growth by inhibiting NF-κB activation

JG3, a novel marine-derived oligosaccharide, significantly inhibits angiogenesis and tumor metastasis by blocking heparanase activity. It also arrests tumor growth, an effect that is not fully explained by its anti-heparanase activity. Here we sought to identify the mechanisms underlying JG3-mediated inhibition of tumor growth. Heparanase expression was assessed by RT-PCR and Western blotting. NF-kappaB activation status was determined using immunofluorescence, Western blotting, DNA-binding and transcription-activity assays. The effect of JG3 on upstream components of the NF-kappaB pathway and on selected transcription factors were monitored by Western blotting. The antitumor effect of JG3 and its relation to NF-kappaB activation were evaluated using four different tumor xenograft models. We found that JG3 effectively inhibited NF-kappaB activation independent of heparanase expression. Our results indicate that JG3 inactivated NF-kappaB by interfering with the activation of upstream components of the NF-kappaB pathway without generally affecting the nuclear translocation of transcription factors. Further, in vivo studies demonstrated that JG3 effectively arrested the growth of tumors derived from cell lines in which NF-kappaB was constitutively active (BEL-7402 liver carcinoma and MDA-MB-435s breast carcinoma), but did not affect the growth of tumors derived from NF-kappaB-negative cell lines (SGC-7901 gastric cancer and HO-8910 ovarian carcinoma). Our data indicate that NF-kappaB mediates the JG3-induced arrest of tumor growth. These results define a new mechanism of action of JG3 and highlight the potential for JG3 as a promising lead molecule in cancer therapy.

Thiol-dependent DNA cleavage by aminomethylated Beaucage's reagent

Aminomethylated Beaucage's reagent 1 was found to be more potent than 3H-1,2-benzodithiol-3-one 1,1-dioxide (Beaucage's reagent) in causing DNA cleavage. The current study demonstrated the importance of the amino functionality in enhancing DNA-cleaving activities, and such findings may facilitate development of novel sulfur-containing DNA-cleaving molecules in cancer therapy.

Heat-Shock Protein 90 Inhibitors in Cancer Therapy: 17AAG and Beyond

Heat-shock protein 90 (HSP90) has diverse functions in mammalian cells. It acts as molecular chaperone, together with several co-chaperone molecules (such as Hop, Hip, p23, cdc37, Aha, and immunophilins). HSP90 binds to its client proteins (such as steroid receptors, AKT, Bcr-Abl, Apaf-1, survivin, cyclin dependent kinases which are involved in signal transduction that regulate cell cycle, survival, and death, and promote their proper protein folding, assembly, and transportation across different cellular compartments. Failure of Hsp90 chaperone activity leads to misfolding of client proteins, which leads to ubiquitination and proteasome degradation, and this deregulating cellular homeostasis. Since tumor cells frequently overexpress the active form of HSP90, which is more susceptible to inhibition by small molecules such as geldanamycin and its analogs, HSP90 became an attractive target for cancer therapy. This paper will review the recent advances in HSP90-biology and will discuss the emerging role of the HSP90 inhibitors such as 17-allylamino-17 demethoxy-geldanamycin and other HSP-90-directed small molecules in cancer therapy.

740. Replicating Retroviral Vector-Mediated Gene Transfer of the Chemokine, Interferon-Inducible Protein 10 (IP-10) Suppresses Angiogenesis and Tumor Growth in Mice

The chemokine interferon-inducible protein 10 (IP-10) is proposed to have antitumor activity in vivo on the basis of its immunomodulatory and antiangiogenic effects. However, the utility of this angiostatic molecule in cancer therapy is hampered by difficulties in manufacturing large quantities of recombinant proteins and the cumbersome administration schedules. This study is aimed to explore IP-10 gene-based anticancer therapy using replicating murine leukemia virus (MLV) vectors, the latter used in order to achieve sustained and efficient delivery of this protein in tumors.

ChemInform Abstract: Acetogenins from Annonaceae. Part 84. Synthesis, Spectroscopy, and Cytotoxicity of Glycosylated Acetogenin Derivatives as Promising Molecules for Cancer Therapy.

AbstractChemInform 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.