Broad-spectrum Anticancer Activity Research Articles

Rapid Cytotoxicity of Antimicrobial Peptide Tempoprin-1CEa in Breast Cancer Cells through Membrane Destruction and Intracellular Calcium Mechanism

Temporin-1CEa is an antimicrobial peptide isolated from the skin secretions of the Chinese brown frog (Rana chensinensis). We have previously reported the rapid and broad-spectrum anticancer activity of temporin-1CEa in vitro. However, the detailed mechanisms for temporin-1CEa-induced cancer cell death are still weakly understood. In the present study, the mechanisms of temporin-1CEa-induced rapid cytotoxicity on two human breast cancer cell lines, MDA-MB-231 and MCF-7, were investigated. The MTT assay and the LDH leakage assay indicated that one-hour of incubation with temporin-1CEa led to cytotoxicity in a dose-dependent manner. The morphological observation using electronic microscopes suggested that one-hour exposure of temporin-1CEa resulted in profound morphological changes in both MDA-MB-231 and MCF-7 cells. The membrane-disrupting property of temporin-1CEa was further characterized by induction of cell-surface exposure of phosphatidylserine, elevation of plasma membrane permeability and rapid depolarization of transmembrane potential. Moreover, temporin-1CEa evoked intracellular calcium ion and reactive oxygen species (ROS) elevations as well as collapse of mitochondrial membrane potential (Δφm). In summary, the present study indicates that temporin-1CEa triggers rapid cell death in breast cancer cells. This rapid cytotoxic activity might be mediated by both membrane destruction and intracellular calcium mechanism.

Design and synthesis of novel 1,2,3-triazole-dithiocarbamate hybrids as potential anticancer agents

A series of novel 1,2,3-triazole-dithiocarbamate hybrids were designed, synthesized and evaluated for anticancer activity against four selected human tumor cell lines (MGC-803, MCF-7, PC-3, EC-109). Majority of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 3a and 3c showed excellent broad spectrum anticancer activity with IC50 values ranging from 0.73 to 11.61 μM and 0.49–12.45 μM, respectively. Particularly, compound 3a was more potent than 5-fluorouracil against all tested human cancer cell lines. Flow cytometry analysis demonstrated that treatment of MGC-803 with 3c led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death after 12 h.

The syntheses and characterizations of vanadium complexes with 1,2-dihydroxyanthraquinone and the structure–effect relationship in their in vitro anticancer activities

[V(V)O2(O2C14H6O2)(C5N2H12)](C5N2H13)(CH3OH) (1) and {Na[V(V)O(O2C14H6O2)2][(CH3)2NCHO]}n (2) have been synthesized by the reaction of V2O5 and NaVO3 with aromatic 1,2-diol (1,2-dihydroxyanthraquinone), and their molecular and crystal structures have been determined by X-ray diffraction. MTT assay tests of the V(V)O2L(A)L(B) and V(V)OL2 complexes against cancer cells have revealed that, when L is catechol, VOL2 showed broad-spectrum, high anticancer activities which were proportional to their concentration; however when L is naphthol or alizarin, VOL2 displayed little effect towards the cancer cells; moreover, complex 1 in the coordination model of V(V)O2L(A)L(B) showed specifically higher inhibition (88.65%) against HCT-8 than the clinical anticancer drug Fu-5 (69.97%). The results revealed that both the V(V) and the ligands cannot influence the inhibition against cancer cells individually. The mechanism of the broad-spectrum anticancer activities of VOL2 when L is catechol ligand might originate from the redox activities of V(V)/V(IV) which regulate the concentration of ROS (reactive oxygen species). N-Methylpiperazine formed as a by-product in complex 1 was confirmed by (1)H NMR and its formation mechanism catalyzed by V2O5 has been deduced.

DIMming Ovarian Cancer Growth

Ovarian cancer is the leading gynecologic malignancy with more than 22,000 new cases and 15,000 deaths estimated each year. It is usually detected in late stages with poor prognosis due to lack of sufficiently accurate screening tests. Epidemiological studies continue to support the notion that consumption of cruciferous vegetables reduces the risk of ovarian cancer. In the present review article, we describe the anti-cancer effects of 3, 3'-diindolylmethane (DIM), a compound present in cruciferous vegetables, against ovarian cancer. DIM targets multiple aspects of cancer such as cellcycle regulation and survival, including EGFR-JAK2-STAT3 signaling, checkpoint activation, caspase activation, endoplasmic reticulum stress, autophagy and anoikis. This broad spectrum of anti-cancer activities in conjunction with low systemic toxicity accentuates the translational value of DIM in cancer therapy. Together, our pre-clinical studies demonstrate that DIM has activity against ovarian cancer and hence should be further investigated in clinical setting to exploit its therapeutic potential.

Synthesis and characterization of daunorubicin modified ZnO/PVP nanorods and its photodynamic action

Abstract Nanomaterials have widely been used in the field of biological and biomedicine, such as tissue imaging, diagnosis and cancer therapy. The aim of this study is to investigate cytotoxicity and photodynamic effect of combined application of polyvinyl pyrrolidone (PVP) modified ZnO nanorods with anticancer drug daunorubicin (DNR) in photodynamic therapy (PDT). Daunorubicin (DNR) has a broad spectrum of anticancer activity, but it is limited in clinical application due to its serious side effects. In DNR-ZnO/PVP nanocomposites, ZnO/PVP nanorods act as drug carrier of DNR in drug delivery system (DNR-ZnO/PVP nanocomposites). This drug delivery system induced remarkable improvement in anticancer activity, as demonstrated by MTT assay using 3-(4,5-dimethylthiazol-2yl)-2,5 diphenyl tetrazolium bromide (MTT reagent). This has been also demonstrated by antibacterial activity and DNA cleavage study. The findings suggest that DNR delivery strategy is a promising approach to cancer therapy.

Enantioselective apoptosis induction in histiocytic lymphoma cells and acute promyelocytic leukemia cells

The aim of this study was to identify valproic acid (VPA) analogs with a broad spectrum of anti-cancer activities and an increased apoptosis-inducing potential compared with the parent VPA, which is enrolled as histone deacetylase (HDAC) inhibitor in a large number of clinical trials. We identified a chiral VPA derivative, (S)-2-pentyl-4-pentynoic acid, previously characterized as HDAC inhibitor that induced massive programmed cell death in a strongly enantioselective manner in U937 histiocytic lymphoma cells and NB4 acute promyelocytic leukemia cells. By performing fluorescence-activated cell sorting and Western blotting analyses, we established that enantiomer (S)-2-pentyl-4-pentynoic acid has higher apoptosis-inducing potential than VPA itself. The optic antipode (R)-2-pentyl-4-pentynoic acid and VPA caused under the same conditions only a weak growth inhibition without inducing cell differentiation and apoptosis. (S)-2-pentyl-4-pentynoic acid is more apoptogenic than VPA and displays enantioselective anti-cancer properties that warrant further research regarding the mechanistic basis of its activity and its potential use in cancer therapy.

Design, Synthesis, and Preliminary Cytotoxicity Evaluation of New Diarylureas and Diarylamides Possessing 1,3,4-Triarylpyrazole Scaffold

A series of new diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold was synthesized and their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-60 cell line panel were tested. Compounds 9, 11, 12, 14, and 17-21 showed superior potency against A375P to Sorafenib. Over the NCI-60 cancer cell line panel, compound 14 possessing a methoxy group, amide linker, and 4-chloro-3-(trifluoromethyl)phenyl terminal ring showed the highest potency and broad-spectrum anticancer activity. Compound 13 showed high selectivity towards leukemia subpanel over other cancer types.

1-(2-Mercaptobenzenesulfonyl)-3-hydroxyguanidines – Novel potent antiproliferatives, synthesis and in vitro biological activity

Twenty four 1-[2-alkylthio-5-(azol-2 or 5-yl)-4-chlorobenzenesulfonyl]-3-hydroxyguanidines 6a–x have been synthesized in order to evaluate their biological activity. Compounds 6a, 6c, 6d, 6f, 6g, 6i–p, 6r–t, and 6v–x were tested for their in vitro anticancer activity at the US National Cancer Institute. The highest in vitro anticancer activity was found for compounds 6d, 6g and 6k with GI50 average value in the range 1.62–1.86 μM, and TGI mean values 3.72–4.47 μM, whereas the remaining compounds showed broad spectrum of anticancer activity at low micromolar GI50 level against all tested cancer cell lines. These results were subjected to CoMSIA analysis to establish quantitative structure–activity relationships. The results evidence that potency of these compounds correlates mainly with hydrophobic and polar surface properties of substituents located both at 2 and 5 positions of 1-(4-chlorobenzenesulfonyl) moiety of investigated 3-hydroxyguanidine series.

Benzimidazole clubbed with triazolo-thiadiazoles and triazolo-thiadiazines: New anticancer agents

Two series of Benzimidazole clubbed with triazolo-thiadiazoles (5a–q, 5r, 5s and 5x–a1) and triazolo-thiadiazines (5t–w) were synthesized with an aim to produce promising anticancer agents. In vitro anticancer activities of synthesized compounds were investigated at the National Cancer Institute (NCI) against NCI 60 cell line panel; results showed good to remarkable broad-spectrum anticancer activity. Among them, the compound 5h (NCS: 760452, 1-(1H-benzo [d] imidazol-2-yl)-3-(6-(2,4-dichlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl) propan-1-one) exhibited significant growth inhibition with GI50 values ranging from 0.20 to 2.58 μM and found superior selectivity for the leukemia cell lines and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM). The 5h may possibly be used as lead compound for developing new anticancer agents.

Abstract 1765: Potent antitumor BO-1922, derivative of indolizino[6,7-b]indole, against human colon, lung, and pancreatic cancers in xenograft model

Abstract Our previously studies demonstrated that bis(hydroxymethyl)cyclopenta[a]indenes, which bear a bis(hydroxymethyl)pyrrolidine pharmacophore, exhibited potent antitumor activity in inhibiting various human tumor xenografts. We also demonstrated that these agents showed strong synergistic therapeutic efficacy in combination with arsenic trioxide (ATO) against acquire or inherited MDR human tumors in xenograft model (human lung H460 or bladder cancer resistant to cisplatin NTUB1/P). Based on these findings, we have recently synthesized a series of 1,2-bis(hydroxymethyl)indolizino[6,7-b]indols and their bis(alkylcarbomate) derivatives for antitumor evaluation. These new agents were easily prepared starting from L-tryptophane in 5 steps. The in vitro cytotoxicity studies showed that the newly synthesized derivatives possessed a broad spectrum of anticancer activity against human lymphoblastic leukemia and various solid tumor cell growth in vitro. Of these analogues, 1,2-bis(hydroxymethyl)-3,6-dimethylindolizino[6,7-b]indole (BO-1922) was selected for further antitumor studies. We found that this agent displayed potent therapeutic efficacy against human colon cancer HT-29, lung adenocarcinoma lung A549, and primary pancreatic adenocarcinoma BX-PC3 xenografts. The antitumor activity of BO-1922 was compared with Irinotecan (CPT-11) in animal xenograft model. It revealed that BO-1922 is more potent than CPT-11 against human colon cancer HT-29 xenograft; complete tumor suppression on day 20 after mice treated with BO-1922 (25 mg/kg, QD×4, intravenous injection), while, tumor relapsed on day 9 after mice treated with CPT-11 (60 mg/kg, Q2D×3, iv. inj.). Under the same drug administration conditions (dosage and schedule), BO-1922 is as potent as CPT-11 against lung cancer A549 and pancreatic cancer BX-PC3 xenografts. Although the bodyweight of all drug treated mice recovered after ceasing of treatment, it was found that BO-1922 is less toxic to the host based on the average body-weight loss. The alkaline agarose gel shifting assay showed that this agent is able to induce DNA double strand cross-linking. Flow cytomeric assay revealed that BO-1922 induced cell cycle arrest at G1/S phase in non-small cell lung carcinomas H1299. These results suggest that BO-1922 is a promising candidate for clinical application and is currently undergoing preclinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1765. doi:1538-7445.AM2012-1765

Abstract 4623: Human anti-nucleolin antibodies with broad spectrum anticancer activity

Abstract Extensive preclinical studies have validated nucleolin as a new therapeutic target in oncology. Confocal microscopy, immunohistochemistry, and cell fractionation studies have shown that this protein is highly overexpressed in the plasma membrane and cytoplasm of a wide variety of human hematological and solid tumor cells, but is usually undetectable on the cell surface or in the cytoplasm of the corresponding normal cells. We have utilized our licensed platform technology to generate a first-in-class panel of eight fully human monoclonal IgG1 antibodies (HuMAbs). These antibodies bind specifically to nucleolin on the tumor cell surface, which in turn elicits potent cytotoxicity to a variety of human tumor cell lines. One such example is CP101, which killed MV4-11 (AML), MCF-7 (breast), DU145 (prostate), PANC-1 and MIA PaCa-2 (pancreas) tumor cell lines with IC50 values ranging from (0.5-2.0 µg/ml; 3-12 nM) following exposure to the HuMAb for 96 hrs. These in vitro assays were performed in the absence of human complement and immune effector cells required for complement-dependent cellular cytotoxicity (CDCC) and antibody-dependent cellular cytotoxicity (ADCC), respectively. These results are consistent with published observations that anti-nucleolin HuMAbs can exploit the known shuttling function of cell surface nucleolin to gain intracellular access and induce direct tumor cytotoxicity. In contrast to its cytocidal effects on tumor cells, CP101 had no effect on the viability of either MCF-10A normal human breast epithelial cells or normal human CD19+ B cells, neither of which expresses nucleolin on the cell surface. In summary, the results suggest that anti-nucleolin HuMAbs are unique in that they can exert broad spectrum antitumor activity independently of the immune mechanism of CDCC and ADCC, while having no detectable effects on the viability of the corresponding normal cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4623. doi:1538-7445.AM2012-4623

Anti-tumour activity of 4-(4-fluorophenyl)amino-5,6,7-trimethoxyquinazoline against tumour cellsin vitro

In order to create novel, potent and selective anti-cancer agents, the action of 4-(4-fluorophenyl)amino-5,6,7-trimethoxyquinazoline (compound 1018) on 10 different kinds of tumour cells were assayed by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide]. It possesses a broad spectrum of anti-cancer activity. The mechanism of action of 4-(4-fluorophenyl)amino-5,6,7-trimethoxyquinazoline (hereafter referred to as compound 1018) against tumour cells was studied in androgen-independent prostate cancer PC-3 cells by microscopic observation, LDH (lactate dehydrogenase) release assay and Western blotting. Its activity was dose-dependent, with an IC50 of 13.0±1.4 μM after 72 h treatment. Microscopy and LDH release assay indicated that the effect was through anti-proliferation rather than cytotoxicity. Western blot analysis also showed that treatment of cells with 50 μM compound 1018 for 30 min almost completely inhibited EGF (epidermal growth factor)-induced phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2), which suggests that its anti-proliferative effect is largely associated due to ERK1/2 activation being inhibited. Thus compound 1018 is a potential anti-cancer agent.

Novel microtubule-targeted agent 6-chloro-4-(methoxyphenyl) coumarin induces G2-M arrest and apoptosis in HeLa cells

To identify a novel coumarin analogue with the highest anticancer activity and to further investigate its anticancer mechanisms. The viability of cancer cells was investigated using the MTT assay. The cell cycle progression was evaluated using both flow cytometric and Western blotting analysis. Microtubule depolymerization was observed with immunocytochemistry in vivo and a tubulin depolymerization assay in vitro. Apoptosis was demonstrated using Annexin V/Propidium Iodide (PI) double-staining and sub-G(1) analysis. Among 36 analogues of coumarin, 6-chloro-4-(methoxyphenyl) coumarin showed the best anticancer activity (IC(50) value about 200 nmol/L) in HCT116 cells. The compound had a broad spectrum of anticancer activity against 9 cancer cell lines derived from colon cancer, breast cancer, liver cancer, cervical cancer, leukemia, epidermoid cancer with IC(50) value of 75 nmol/L-1.57 μmol/L but with low cytotocitity against WI-38 human lung fibroblasts (IC(50) value of 12.128 μmol/L). The compound (0.04-10 μmol/L) induced G(2)-M phase arrest in HeLa cells in a dose-dependent manner, which was reversible after the compound was removed. The compound (10-300 μmol/L) induced the depolymerization of purified porcine tubulin in vitro. Finally, the compound (0.04-2.5 μmol/L) induced apoptosis of HeLa cells in dose- and time-dependent manners. 6-Chloro-4-(methoxyphenyl) coumarin is a novel microtubule-targeting agent that induces G(2)-M arrest and apoptosis in HeLa cells.

Daunorubicin-TiO2 nanocomposites as a “smart” pH-responsive drug delivery system

Daunorubicin (DNR) has a broad spectrum of anticancer activity, but is limited in clinical application due to its serious side effects. The aim of this study was to explore a novel “smart” pH-responsive drug delivery system (DDS) based on titanium dioxide (TiO2) nanoparticles for its potential in enabling more intelligent controlled release and enhancing chemotherapeutic efficiency of DNR. DNR was loaded onto TiO2 nanoparticles by forming complexes with transition metal titanium to construct DNR-TiO2 nanocomposites as a DDS. DNR was released from the DDS much more rapidly at pH 5.0 and 6.0 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. DNR-TiO2 nanocomposites induced remarkable improvement in anticancer activity, as demonstrated by flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and nuclear 4′,6-diamidino- 2-phenylindole staining. Furthermore, the possible signaling pathway was explored by western blot. For instance, in human leukemia K562 cells, it was demonstrated that DNR-TiO2 nanocomposites increase intracellular concentration of DNR and enhance its anticancer efficiency by inducing apoptosis in a caspase-dependent manner, indicating that DNR-TiO2 nanocomposites could act as an efficient DDS importing DNR into target cancer cells. These findings suggest that “smart” DNR delivery strategy is a promising approach to cancer therapy.

Phenylarsonic acid compounds with broad-spectrum and potent cytotoxic activity against human cancer cells.

The in vitro cytotoxic activity profile of nine novel phenylarsonic acid (CAS 98-05-5, PAA) compounds against 17 human cancer cell lines including (a) ovarian cancer cell lines ES-2, PA-1, CAOV-3, OVCAR-3, (b) testicular cancer cell lines Ntera-2, Tera-2, N2NICP, 833K, and 64CP, (c) multiple myeloma cell lines ARH77, HS-Sultan, RPMI-8226, and U266, and (d) acute lymphoblastic leukemia (ALL) cell lines NALM-6, MOLT-3, ALL-1, and RS4; 11, was determined by the MTT assay. The lead compounds, 2-methylthio-4-[(4'-aminophenylazo)-phenylarsonic acid] pyrimidine (PHI-370) and 2-methylthio-4-(4'-phenylarsonic acid)-aminopyrimidine (PHI-380) caused apoptotic death in all 17 cancer cell lines at low micromolar concentrations, as documented by TUNEL assays and confocal laser scanning microscopy. PHI-380 was also tested and found to be very active against primary tumor cells isolated from surgical biopsy specimens of 14 patients with therapy-refractory non-small cell lung cancer, breast cancer, colon cancer, lymphoma, hepatoblastoma, or Wilm's tumor as well. Because of their broad-spectrum and potent anticancer activity and ability to induce apoptosis in primary tumor cells from therapy-refractory cancer patients, PAA compounds such as PHI-370 and PHI-380 may provide the basis for effective salvage regimens for patients with recurrent cancer.

Anticancer activity of an extract from needles and twigs of Taxus cuspidata and its synergistic effect as a cocktail with 5-fluorouracil

BackgroundBotanical medicines are increasingly combined with chemotherapeutics as anticancer drug cocktails. This study aimed to assess the chemotherapeutic potential of an extract of Taxus cuspidata (TC) needles and twigs produced by artificial cuttage and its co-effects as a cocktail with 5-fluorouracil (5-FU).MethodsComponents of TC extract were identified by HPLC fingerprinting. Cytotoxicity analysis was performed by MTT assay or ATP assay. Apoptosis studies were analyzed by H & E, PI, TUNEL staining, as well as Annexin V/PI assay. Cell cycle analysis was performed by flow cytometry. 5-FU concentrations in rat plasma were determined by HPLC and the pharmacokinetic parameters were estimated using 3p87 software. Synergistic efficacy was subjected to median effect analysis with the mutually nonexclusive model using Calcusyn1 software. The significance of differences between values was estimated by using a one-way ANOVA.ResultsTC extract reached inhibition rates of 70-90% in different human cancer cell lines (HL-60, BGC-823, KB, Bel-7402, and HeLa) but only 5-7% in normal mouse T/B lymphocytes, demonstrating the broad-spectrum anticancer activity and low toxicity to normal cells of TC extract in vitro. TC extract inhibited cancer cell growth by inducing apoptosis and G2/M cell cycle arrest. Most interestingly, TC extract and 5-FU, combined as a cocktail, synergistically inhibited the growth of cancer cells in vitro, with Combination Index values (CI) ranging from 0.90 to 0.26 at different effect levels from IC50 to IC90 in MCF-7 cells, CI ranging from 0.93 to 0.13 for IC40 to IC90 in PC-3M-1E8 cells, and CI < 1 in A549 cells. In addition, the cocktail had lower cytotoxicity in normal human cell (HEL) than 5-FU used alone. Furthermore, TC extract did not affect the pharmacokinetics of 5-FU in rats.ConclusionsThe combinational use of the TC extract with 5-FU displays strong cytotoxic synergy in cancer cells and low cytotoxicity in normal cells. These findings suggest that this cocktail may have a potential role in cancer treatment.

Immunomodulatory Properties of Thalidomide Analogs: Pomalidomide and Lenalidomide, Experimental and Therapeutic Applications

Thalidomide has a broad spectrum of anti-cancer activity. Antitumor activity of thalidomide may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-α and T-cell costimulatory and antiangiogenic activities. The therapeutic potential of thalidomide provided motivation to develop more effective derivatives with considerably reduced toxicity. Thalidomide's immunomodulatory (IMiDs) analogs (lenalidomide, CC-5013; CC-4047, ACTIMID) represent a novel class of compounds with numerous effects on the immune system. Some of these analogs are thought to mediate the anticancer and anti-inflammatory effects observed in humans. Thalidomide is currently approved for the treatment of dermal reaction to leprosy and is currently in phase III trials for multiple myeloma (MM). IMiDs inhibit the cytokine's tumor necrosis factor-α (TNF-α), interleukins (IL) 1β, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). The repression of the tumor necrosis factor-a (TNF-α) expression is the crucial factor of many of the anti-inflammatory properties of thalidomide. The mechanisms underlying many of the anti-inflammatory properties of thalidomide, including its ability to co-stimulate T cells, still remain unclear. Some recent patent are also summarized in this review.

Abstract 2542: Preclinical studies of novel phosphonium salts with broad-spectrum activity

Abstract Proliferation under selective pressures exerted by an unstable microenvironment, requires tumor cells employ adaptive mechanisms that confer growth advantage. Adaptation to adverse conditions results in cellular phenotypes that typify neoplastic transformation and offer unique opportunities for selective targeting of cancer cells. Agents that target tumor cell mitochondria with high selectivity hold clinical significance due to the adaptive, modulatory and essential role of this organelle in cancer cell energy production, metabolism and apoptosis. To this end, we have identified a series of novel, mitochondriotropic phosphonium salts, (TP compounds), that have shown broad-spectrum anti-cancer and anti-angiogenic activity in preclinical evaluation. A high-throughput MTT-based screen of over 10,000 drug-like small molecules for anti-proliferative activity identified the phosphonium salts TP187, 197 and 421 and numerous close analogues as having IC50 concentrations in the sub-micromolar range. TP treatment induced cell cycle arrest, lowered oxygen consumption, and increased mitochondrial superoxide production. Administered as single agents in a mouse model of human breast cancer, TP compounds significantly decreased tumor growth with no observed toxicities. Protein microarray data demonstrated significant down-regulation of integrin and growth factor mediated signaling pathways governing key processes including cancer cell survival, proliferation and tumor angiogenesis. At low micromolar concentrations, TP compounds prevented integrin-mediated cell adhesion to fibronectin and vitronectin coated substrates and tumor cell haptotaxsis on vitronectin coated boyden chambers. Similar concentrations of TP compound also prevented growth factor induced endothelial cell tube formation in 3-D culture using basement membrane extracts. Taken together, these results suggest that as mitochondria-targeted agents, TP compounds act to inhibit tumor cell proliferation and angiogenic capacity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2542. doi:10.1158/1538-7445.AM2011-2542

Synthesis and in vitro antitumor activity of new butenolide-containing dithiocarbamates

Three series of butenolide-containing dithiocarbamates were designed and synthesized. Their anti-tumor activity in vitro was evaluated. Among them compound I-14 exhibited broad spectrum anti-cancer activity against five human cancer cell lines with IC(50) <30 μM. Structure-activity relationship analysis showed that the introduction of dithiocarbamate side chains on the C-3 position of butenolide was crucial for anti-tumor activity.

Telomeres as targets for anticancer therapies

Introduction: The limitless replicative potential of cancer cells relies on telomere integrity (which is guaranteed by a complex interaction between several specialized proteins and telomeric DNA) and the activation of specific mechanisms for telomere length maintenance. Two mechanisms are currently known in human cancer, namely telomerase activity and the alternative lengthening of telomere pathway.Expert opinion: In this review, we summarize the available data concerning the therapeutic strategies proposed thus far and the current challenges posed for the development of innovative telomere-based therapeutic approaches with broad-spectrum anticancer activity and for their translation into the clinical setting.Areas covered: Due to their essential role in tumor cell proliferation, telomere maintenance mechanisms have become extremely attractive targets for the development of new anticancer interventions. Although numerous efforts have been made to identify specific approaches to interfere with telomere maintenance mechanisms in human cancers, the only molecule currently tested in clinical trials is the oligonucleotide GRN163L. However, a growing body of evidence suggests that interfering with telomeres, through the direct targeting of telomeric G-quadruplex structures, may be a valuable antitumor therapeutic strategy, independent of the specific telomere maintenance mechanism operating in the tumor.