Selective Antiproliferative Effects Research Articles

1,2,4-Triazolin-5-thione derivatives with anticancer activity as CK1γ kinase inhibitors.

The optimization and synthesis of new CK2 and CK1 inhibitors are the basis for the development of new therapeutic strategies for the treatment of cancer and neurodegenerative disorders associated with overexpression and abnormal functioning of these enzymes. Triazole derivatives appear to be especially interesting as potential kinase inhibitors. In this context we synthesized a series of 1,2,4-triazolin-5-thione derivatives as CK1γ kinase inhibitors. The antiproliferative activity of synthesized compounds was assessed against cancer cells: human lung adenocarcinoma (A549), human hepatoma (HepG2), and human breast adenocarcinoma (MCF-7). Compound 1 exhibited antiproliferative potency against A549 cancer cells and was characterized by a selective antiproliferative effect. Additionally, this compound has high apoptotic activity against A549, HepG2, MCF-7 cells and induced only slight amount of necrotic cells in these cell lines. In order to decipher the mechanism of anticancer activity of the studied compounds PASS software was used and these compounds were assayed for the inhibition of CK1γ and CK2α kinases. The reported series of 1,2,4-triazolin-5-thiones inhibits CK1γ and CK2α kinases in micromolar range. The most active compound shows activity against isoform γ3 which at concentration of 50μM reduced the kinase activity by 69% while at 100μM by 80%. CK2α was found to be less susceptible to the effects of the triazoles tested, as the reduction in kinase activity by 29% was observed for compound 15, and by 27% for compound 1 only at the concentration of 100μM. The inhibition of CK1γ and CK2α kinases was rationalized using molecular docking.

Mixed-Generation PAMAM G3-G0 Megamer as a Drug Delivery System for Nimesulide: Antitumor Activity of the Conjugate Against Human Squamous Carcinoma and Glioblastoma Cells.

Polyhydroxylated dendrimer was synthesized from poly(amidoamine) (PAMAM) dendrimer generation 3 by addition of glycidol (G3gl). G3gl megamer was further modified by binding PAMAM G0 dendrimers by activation of G3gl with p-nitrophenylchloroformate, followed by the addition of excess PAMAM G0 and purification using dialysis. The maximum G0 binding capacity of G3gl was 12 in the case when G0 was equipped with two covalently attached nimesulide equivalents. Nimesulide (N) was converted into N-(p-nitrophenyl) carbonate derivative and fully characterized using X-ray crystallography and spectral methods. Nimesulide was then attached to G0 via a urea bond to yield G02N. The mixed generation G3gl–G02N megamer was characterized using 1H NMR spectroscopy, and its molecular weight was estimated to be 22.4 kDa. The AFM image of G3gl–G02N deposited on mica demonstrated aggregation of nimesulide-covered megamer. The height of the deposited megamer was 8.5 nm. The megameric conjugate with nimesulide was tested in vitro on three human cell lines: squamous cell carcinoma (SCC-15) and glioblastoma (U-118 MG) overexpressing cyclooxygenase-2 (COX-2), and normal skin fibroblasts (BJ). The conjugate efficiently penetrated into all cells and was more cytotoxic against SCC-15 than against BJ. Moreover, the conjugate produced a strong and selective antiproliferative effect on both cancer cell lines (IC50 < 7.5 µM).

Platyphylloside Isolated from Betula platyphylla is Antiproliferative and Induces Apoptosis in Colon Cancer and Leukemic Cells.

Betula platyphylla bark has been evaluated for the treatment of dermatitis, inflammatory conditions, and cancer. Diarylheptanoids are the major constituents of the B. platyphylla bark and possess various pharmacological effects. Our previous study confirmed the selective antiproliferative effect of platyphylloside (BPP) isolated from B. platyphylla on colon cancer and leukemic cells using 60 different cancer cell lines from thr National Cancer Institution (NCI). In line with previous reports, this study focuses on the apoptotic pathway of BPP, a phenolic glycoside composed of two aromatic rings joined by a seven-carbon chain. Cytotoxicity assays in solid tumor and blood cancer cell models demonstrated that BPP possesses potent antiproliferative activity. The level of apoptosis increased with BPP treatment, causing cell cycle arrest at the G1 phase along with the downregulation of IκBα phosphorylation and BCL-2, as well as upregulation of cleaved caspase 3 and BAX proteins. In addition, BPP displayed potent mitochondrial depolarization effects in Jurkat cells. The combined findings revealed that the cytotoxic effects of BPP were mediated by intracellular signaling, possibly through a mechanism involving the upregulation of mitochondrial reactive oxygen species (ROS). Thus, BPP could be a potential multitarget therapeutic agent in leukemia and colon cancer.

RNA G-quadruplex as supramolecular carrier for cancer-selective delivery

Nucleic acid aptamers have emerged as an attractive class of carrier molecules due to their ability to bind with high affinity to specific ligands; their high chemical flexibility; as well as tissue penetration capability. RNA G-quadruplex (rG4) sequences have been described as structures with high stability and selectivity towards cancer cells. Recently, precursor microRNAs (pre-miRNAs) have been described as new G4 forming molecules. Surface nucleolin (NCL) is a known target of aptamer G4 AS1411 and is overexpressed on prostate cancer cells when compared with normal cells. We have shown that the sequence 5′ GGGAGGGAGGGACGGG 3′ found in pre-miR-149 forms a rG4 parallel structure, which can bind NCL. Also, another rG4 sequence with a longer loop was evaluated in terms of G4 formation, stabilization and binding affinity to NCL.Both rG4s sequences were studied as supramolecular carriers for the cancer-selective delivery of acridine ligand C8. The rG4s-C8 complexes showed high affinity (KD = 10−6 M) and stabilization (Tm > 30 °C). The affinity of the rG4s-C8 complexes against NCL was in the low nanomolar range, indicating that C8 did not affect NCL binding. Noteworthy, the short loop rG4-C8 complex showed selective antiproliferative effects in prostate cancer cells when compared with normal prostatic cells. The stability and nuclease resistance of rG4 and rG4-C8 complex were evaluated in biological conditions and revealed the maintenance of G4 structure and complex stability. Furthermore, confocal microscopy studies confirmed the potential of rG4s-C8 complexes in the targeting of prostate cancer cells.Overall, it is here demonstrated that the rG4 found in pre-miR-149 can be used as a cancer-selective delivery carrier of C8 to prostate cancer cells.

Schiff base-nickel, palladium, and platinum complexes derived from N-cyclohexyl hydrazine carbothioamide and 3-hydroxy-4-methoxybenzaldehyde: Selective antiproliferative and proapoptotic effects against colorectal carcinoma.

The bidentate N-cyclohexyl-2-(3-hydroxy-4-methoxybenzylidene)hydrazine-1-carbothioamide Schiff base ligand (HL) was coordinated to divalent nickel, palladium and platinum ions to form square planar complexes. The nickel and palladium complexes, [NiL2 ], [PdL2 ] form square planar complexes with 2:1 ligand to metal ratio. The platinum complex, [PtL(dmso)Cl] formed a square planar complex with 1:1 ligand to metal ratio. Platinum undergoes in situ reaction with DMSO before complexing with the ligand in solution. The cytotoxicity of HL, [NiL2 ], [PdL2 ], and [PtL(dmso)Cl] were evaluated against human colon cancer cell line (HCT-116), human cervical cancer (Hela) cell line, melanoma (B16F10) cells, and human normal endothelial cell lines (Eahy926) by MTT assay. The [NiL2 ] complex displayed selective cytotoxic effect against the HCT 116 cancer cell line with IC50 of 7.9 ± 0.2 μM. However, HL, [PdL2 ], and [PtL(dmso)Cl] only exhibited moderate cytotoxic activity with IC50 = 75.9 ± 2.4, 100.0 ± 1.8, and 101.0 ± 3.6 μM, respectively. The potent cytotoxicity of [NiL2 ] was characterized using Hoechst and Rhodamine assays. The nickel complex, [NiL2 ], caused remarkable nuclear condensation and reduction in mitochondrial membrane potential. In addition, molecular docking studies confirms that [NiL2 ] possesses significant binding efficiency with Tyrosine kinase. Altogether, the results revealed that [NiL2 ] exhibits cytotoxicity against the cancer cells via Tyrosine kinase-induced proapoptosis pathway. This study demonstrates that the [NiL2 ] complex could be a promising therapeutic agent against colorectal carcinoma.

Fluorinated Polymer Mediated Transmucosal Peptide Delivery for Intravesical Instillation Therapy of Bladder Cancer.

Surgical intervention combined with intravesical instillation of chemotherapeutics to clear residual cancer cells after operation is the current standard treatment method for bladder cancer. However, the poor bioavailability of active pharmaceutical ingredients for bladder cancer cells on account of the biological barriers of bladder mucosa, together with significant side effects of currently used intravesical medicine, have limited the clinical outcomes of localized adjuvant therapy for bladder cancer. Aiming at improved intravesical instillation therapy of bladder cancer, a fluorinated polyethylenimine (F-PEI) is employed here for the transmucosal delivery of an active venom peptide, polybia-mastoparan I (MPI), which shows selective antiproliferative effect against various bladder cancer cell lines. Upon simple mixing, MPI and F-PET would coassemble to form stable nanoparticles, which show greatly improved cross-membrane and transmucosal penetration capacities compared with MPI alone or nonfluorinated MPI/PEI nanoparticles. MPI/F-PEI shows higher in vivo tumor growth inhibition efficacy for local treatment of a subcutaneous tumor model. More excitingly, as further demonstrated in an orthotopic bladder cancer model, MPI/F-PEI offers remarkably improved therapeutic effects compared to those achieved by free MPI or the first-line bladder cancer drug mitomycin C. This work presents a new transmucosal delivery carrier particularly promising for intravesical instillation therapy of bladder cancer.

Stabilized Peptide HDAC Inhibitors Derived from HDAC1 Substrate H3K56 for the Treatment of Cancer Stem-Like Cells In Vivo.

FDA-approved HDAC inhibitors exhibit dose-limiting adverse effects; thus, we sought to improve the therapeutic windows for this class of drugs. In this report, we describe a new class of peptide-based HDAC inhibitors derived from the HDAC1-specific substrate H3K56 with improved nonspecific toxicity compared with traditional small-molecular inhibitors. We showed that our designed peptides exerted superior antiproliferation effects on cancer stem-like cells with minimal toxicity to normal cells compared with the small-molecular inhibitor SAHA, which showed nonspecific toxicity to normal and cancer cells. These peptide inhibitors also inactivated cellular HDAC1 and HDAC6 and disrupted the formation of the HDAC1, LSD1, and CoREST complex. In ovarian teratocarcinoma (PA-1) and testicular embryonic carcinoma (NTERA-2) cell xenograft animal models (5 mice/group, 50 mg/kg, every other day, intraperitoneal injection), these peptides inhibited tumor growth by 80% to 90% with negligible organ (heart, liver, spleen, lung, kidney, brain) lesions. These results represent the first attempt to design chemically stabilized peptide inhibitors to investigate HDAC inhibition in cancer stem-like cells. These novel peptide inhibitors have significantly enhanced therapeutic window and offer promising opportunities for cancer therapy. SIGNIFICANCE: Selective antiproliferative effects of stabilized peptide HDAC inhibitors toward cancer stem-like cells provide a therapeutic alternative that avoids high nonspecific toxicity of current drugs.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1769/F1.large.jpg.

Structural, computational and anticancer activity studies of D-seco-17-mesyloxy androstane derivatives

Sulfonates express a variety of biological and pharmacological activities, which indicates them as compounds of interest, in both synthetic and biological research areas. Among sulfonates, mesylates (methanesulfonyloxy compounds) draw attention by their physicochemical and biological properties, as well as by their reactivity. Here we present X-ray and computational study of 3β-acetoxy-17-methanesulfonyloxy-16,17-secoandrost-5-ene-16-nitrile (1) and its anti-proliferative activity against five common human cancer cell lines. Computational study includes geometry optimization, frontier molecular orbital analysis and molecular electrostatic potential mapping at the PW6B95-D3BJ/Def2-TZVP level of theory. Studied mesylate compound 1 expressed quite strong selective anti-proliferative effect against human breast and prostate cancer cell lines. Anticancer activity of this compound was compared to its 17-methyl analogs (compounds 2 and 3). Computational study of d-secoandrostane compounds 1–3 allowed us to presume the structural features, important for their chemical reactivity. The differences between the antiproliferative activity of d-secomesylate compound 1 and its 17-methyl analogs 2 and 3 could be explained by possible mechanism in the cancer cells.

Anti-oxidant and Selective Anti-proliferative Effects of the Total Cornicabra Olive Polyphenols on Human Gastric MKN45 Cells.

BackgroundAccording to the epidemiological studies, consuming olive products can decrease the incidence of the different types of cancers mostly due to the high anti-oxidant properties of their polyphenolic compounds.ObjectivesTo evaluate the anti-oxidant and anti-proliferative potentials of the olive fruits total polyphenols on the gastric adenocarcinoma MKN45 cells in comparison to the normal Hu02 cells.Materials and MethodsThe total phenolic content of the olive fruits and radical scavenging activity were determined by Folin and 2,2-diphenyl-1-picrylhydrazyl (DPPH) tests respectively. MTT assay was performed for the evaluation of the cell viability. Intracellular reactive oxygen species (ROS) level was measured using DCFH-DA. Statistical analysis was performed using SPSS 16 statistical software.ResultsTreatment of the MKN45 cells with the phenolic compounds extracted from olive fruits decreased growth and viability of the cells in a dose- and time-dependent manner. In addition, treatment of the MKN45 cells with a combination of the phenolic compounds extracts and cytarabine further decreased cell compared to monotherapy of the cells with each compound alone. Mechanistically, we showed that the anti-cancer effects of the olive polyphenols in the MKN45 cells are mediated through depletion of ROS. Similarly, polyphenolic extracts were found to decrease ROS level in the normal cells at the concentrations of 500 and 1000 μg.mL-1 and short treatment times (6 h), but the viability of these cells did not significantly change. At high concentrations (2000 μg.mL-1) of the phenolic extracts or at longer times of incubation (12 h), however, both ROS levels and the viability of the cells were significantly decreased in the normal cells.ConclusionsThe olive fruits polyphenolic extract modulates ROS levels and selectively targets cancerous cells at low concentrations. Also, the effects of cytarabine could be potentiated by the olive fruits polyphenols. Thus, for a combined protocol of cancer cell therapy, olive fruit polyphenolic compound could be proposed as a proper candidate.

Anti-proliferative effect of auriculataoside A on B16 melanoma 4A5 cells by suppression of Cdc42-Rac1-RhoA signaling protein levels.

Auriculataoside A, an anthracenone dimer glycoside isolated from Cassia auriculata seed, shows anti-proliferative effects on cell line B16 melanoma 4A5 cells with an IC50 value of 0.82μM. However, it shows no such effect on normal human dermal fibroblast (HDF) cells. To evaluate the mode of action underlying the anti-proliferative effect of auriculataoside A on cells, we examined changes in whole protein expression after treatment with auriculataoside A and found that the expression Cdc42, RhoA, and Rac1, which are Rho family GTPases, was reduced. Auriculataoside A also arrested the cell cycle at G1 phase. These results suggest that the suppression of the above proteins induced G1 arrest. In addition, auriculataoside A also suppressed the expression of β-catenin and c-Myc proteins. This action of auriculataoside A could be one of the mechanisms underlying its selective anti-proliferative effect on B16 melanoma cells.

Syntheses and evaluation of new Quinoline derivatives for inhibition of hnRNP K in regulating oncogene c-myc transcription

Aberrant overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key feature in oncogenesis and progression of many human cancers. hnRNP K has been found to be a transcriptional activator to up-regulate c-myc gene transcription, a critical proto-oncogene for regulation of cell growth and differentiation. Therefore, down-regulation of c-myc transcription by inhibiting hnRNP K through disrupting its binding to c-myc gene promoter is a potential approach for cancer therapy. In the present study, we synthesized and screened a series of Quinoline derivatives and evaluated their binding affinity for hnRNP K. Among these derivatives, (E)-1-(4-methoxyphenyl)-3-(4-morpholino-6-nitroquinolin-2-yl)prop-2-en-1-one (compound 25) was determined to be the first-reported hnRNP K binding ligand with its KD values of 4.6 and 2.6 μM measured with SPR and MST, respectively. Subsequent evaluation showed that the binding of compound 25 to hnRNP K could disrupt its unfolding of c-myc promoter i-motif, resulting in down-regulation of c-myc transcription. Compound 25 showed a selective anti-proliferative effect on human cancer cell lines with IC50 values ranged from 1.36 to 3.59 μM. Compound 25 exhibited good tumor growth inhibition in a Hela xenograft tumor model, which might be related to its binding with hnRNP K. These findings illustrated that inhibition of DNA-binding protein hnRNP K by compound 25 could be a new and selective strategy of regulating oncogene transcription instead of targeting promoter DNA secondary structures such as G-quadruplexes or i-motifs.

Evaluation of chemotherapeutic and cancer-protective properties of sphingosine and C2-ceramide in a human breast stem cell derived carcinogenesis model.

The overall goal of the present study was to evaluate the chemotherapeutic and cancer-protective properties of D-erythro-sphingosine (sphingosine) and C2-ceramide using a human breast epithelial cell (HBEC) culture system, which represents multiple-stages of breast carcinogenesis. The HBEC model includes Type I HBECs (normal stem), Type II HBECs (normal differentiated) and transformed cells (immortal/non-tumorigenic cells and tumorigenic cells, which are transformed from the same parental normal stem cells). The results of the present study indicate that sphingosine preferentially inhibits proliferation and causes death of normal stem cells (Type I), tumorigenic cells, and MCF7 breast cancer cells, but not normal differentiated cells (Type II). In contrast to the selective anti-proliferative effects of sphingosine, C2-ceramide inhibits proliferation of normal differentiated cells as well as normal stem cells, tumorigenic cells, and MCF7 cancer cells with similar potency. Both sphingosine and C2-ceramide induce apoptosis in tumorigenic cells. Among the sphingosine stereoisomers (D-erythro, D-threo, L-erythro, and L-threo) and sphinganine that were tested, L-erythro-sphingosine most potently inhibits proliferation of tumorigenic cells. The inhibition of breast tumorigenic/cancer cell proliferation by sphingosine was accompanied by inhibition of telomerase activity. Sphingosine at non-cytotoxic concentrations, but not C2-ceramide, induces differentiation of normal stem cells (Type I), thereby reducing the number of stem cells that are more susceptible to neoplastic transformation. To the best of our knowledge, the present study demonstrates one of the first results that sphingosine can be a potential chemotherapeutic and cancer-protective agent, whereas C2-ceramide is not an ideal chemotherapeutic and cancer-protective agent due to its anti-proliferative effects on Type II HBECs and its inability to induce the differentiation of Type I to Type II HBECs.

Bio-Guided Fractionation of Papaya Leaf Juice for Delineating the Components Responsible for the Selective Anti-proliferative Effects on Prostate Cancer Cells.

Alternative therapies against cancer cells with minimal or no effect on healthy tissues are highly sought after. Prostate cancer (PCa) is the second most frequently diagnosed malignancy in males. The Carica papaya L. leaf extract has been traditionally used by Australian aboriginal people for anticancer properties. In this study, medium polar fraction of papaya leaf extract that had shown anti-proliferative activity in PCa cell lines in vitro, in earlier studies, was further fractionated to 28 fractions by semi-preparative HPLC. Nine of these fractions were identified to possess selective anti-proliferative responses on PCa cells in comparison to non-cancerous cells of prostate gland origin. When these nine sub-fractions were mixed in various combinations, a combination containing six of the specific fractions (FC-3) showed the best potency. FC3 inhibited the growth of BPH-1, PC-3, and LNCaP cells in a concentration-dependent manner with an IC50 value <20 μg/mL, while (unlike paclitaxel, the positive control) minimal effect was observed on the proliferation of non-cancerous, WPMY-1 and RWPE-1cells. Furthermore, synergistic interaction of FC-3 with paclitaxel was observed with combination index values in the range of 0.89–0.98 and 0.85–1.10 on PC-3 and LNCaP cells, respectively. Untargeted qualitative analysis using UHPLC (Ultra High-Performance Liquid Chromatography)-QToF (Quadrupole Time of-Flight) mass spectrometry and screening against the METLIN database indicated presence of multiple known anticancer compounds in the FC-3 extract. These outcomes show that the potent and selective anti-proliferative effects are due to a range of bio-active compounds within the medium polar fraction of papaya leaf juice.

Lucidumol D, a new lanostane-type triterpene from fruiting bodies of Reishi (Ganoderma lingzhi)

A new lanostane-type triterpenoid, lucidumol D (1) was isolated from the fruiting bodies of Ganoderma lingzhi. Its structure was elucidated on the basis of extensive 1D- and 2D-NMR studies as well as mass spectrometry. The cytotoxicity of lucidumol D against proliferation of several cancer cells were assayed by using MTT method and the obtained result suggested selective anti-proliferative and cytotoxic effects against MCF-7, HepG2, HeLa, Caco-2, and HCT-116. In comparison to lucidumol C (2) isolated previously by our group, the structure-activity relationship indicated that carbonyl function at C-11 is necessary to enhance the cytotoxicity.

Synthesis and Anti-Proliferative Effects of Mono- and Bis-Purinomimetics Targeting Kinases.

A series of mono-pyrrolo[2,3-d]pyrimidines 4a–4k, unsymmetrical bis-purine isosteres 5a–5e and symmetrical bis-pyrrolo[2,3-d]pyrimidines 6a and 6b connected via di(1,2,3-triazolyl)phenyl linker were synthesized by click chemistry. Whereas mono- 4g and bis-pseudopurine 5e showed selective inhibitory activities on cervical carcinoma (HeLa) cells, bis-pyrrolo[2,3-d]pyrimidine 6b exhibited potent and selective anti-proliferative effect in the nanomolar range on pancreatic carcinoma (CFPAC-1) cells. Among these, compound 6b induced a significant reduction in the expression level of CDK9 (cyclin-dependent kinase 9)/cyclin T1 in CFPAC-1 cells concomitant with attenuation of proliferative signaling mediated by c-Raf (rapidly accelerated fibrosarcoma) and p38 MAP (mitogen-activated protein) kinases. Our findings encourage further development of novel structurally related analog of 6b to obtain more selective anticancer agent for treating pancreatic cancer.

Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization.

PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 μM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0.987 μM. Kinetic experiments indicated that 17 was a SAM competitive inhibitor other than the substrate. In addition, 17 showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. 17 may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications.

Derivatives of alkyl gallate triphenylphosphonium exhibit antitumor activity in a syngeneic murine model of mammary adenocarcinoma

We previously demonstrated that alkyl gallates coupled to triphenylphosphine have a selective and efficient antiproliferative effect by inducing mitochondrial uncoupling in vitro due to the increased mitochondrial transmembrane potential of tumor cells. Therefore, in this work, the in vivo antitumor activities of alkyl gallate triphenylphosphonium derivatives (TPP+C8, TPP+C10 and TPP+C12) were evaluated in a syngeneic murine model of breast cancer. We found that TPP+C10 increased the cytosolic ADP/ATP ratio and significantly increased the AMP levels in a concentration-dependent manner in TA3/Ha murine mammary adenocarcinoma cells. Interestingly, TPP+C10 induced a decrease in the levels of cellular proliferation markers and promoted caspase-3 activation in tumor-bearing mice. Additionally, TPP+C10 inhibited tumor growth in the syngeneic mouse model. Importantly, 30days of intraperitoneal (i.p.) administration of the combination of TPP+C10 (10mg/kg/48h) and the antibiotic doxycycline (10mg/kg/24h) completely eliminated the subcutaneous tumor burden in mice (n=6), without any relapses at 60days post-treatment. This enhancement of the individual activities of TPP+C10 and doxycycline is due to the uncoupling of oxidative phosphorylation by TPP+C10 and the inhibition of mitochondrial biogenesis by doxycycline, as demonstrated by loss of mitochondrial mass and overexpression of PGC1-α as an adaptive response. Moreover, i.p. administration of TPP+C10 (10mg/kg/24h) to healthy mice did not produce toxicity or damage in organs important for drug metabolism and excretion, as indicated by hematological, biochemical and histological assessments. These findings suggest that the combination of TPP+C10 with doxycycline is a valuable candidate therapy for breast cancer management.

Protein kinase C inhibitor chelerythrine selectively inhibits proliferation of triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking targeted therapy currently. Recent studies imply that protein kinase C may play important roles in TNBC development and could be a specific target. In this study, we evaluated the anti-proliferative activity of PKC inhibitor chelerythrine on a panel of breast cancer cell lines. Chelerythrine selectively inhibited the growth of TNBC cell lines compared to non-TNBC cell lines as demonstrated by in vitro cell proliferation assay and colony formation assay, as well as evidenced by in vivo xenograft assay. The selective anti-proliferative effect of chelerythrine was associated with induction of apoptosis in TNBC cell lines. We further demonstrated that PKN2, one of the PKC subtypes, was highly expressed in TNBC cell lines, and knocking down PKN2 in TNBC cells inhibited colony formation and xenograft growth. This indicates that PKN2 is required for the survival of TNBC cells, and could be the target mediates the selective activity of chelerythrine. Finally, combination of chelerythrine and chemotherapy reagent taxol showed synergistic/additive effect on TNBC cell lines. Our results suggest chelerythrine or other PKC inhibitors may be promising regimens for TNBC tumors.

Novel Mechanisms of Resistance to Investigational Molecularly Targeted Drugs.

Drug resistance is a critical problem inhibiting the effective use of targeted molecular cancer therapies. Investigators have revealed a variety of resistance mechanisms, including alterations in drug targets, activation of pro-survival pathways, and the ineffective induction of cell death. The key alterations driving this resistance are likely condition-dependent, and a detailed analysis would be required to characterize these diverse alterations under a variety of conditions in order to facilitate practical precision medicine for treating individual cancer patients. We have been investigating the molecular mechanisms of anti-cancer drug resistance, and analyzed our original resistant cells against anti-mitotic kinase inhibitors. This study suggests that novel mechanisms reduce cytokinetic dysregulation caused by those inhibitors, and anti-apoptotic activities are associated with resistant phenotypes. These observations suggest that the activation of various bypass mechanisms may allow cancer cells to avoid the selective antiproliferative effect of molecularly targeted drugs, and such bypass activation mechanism would thus be a critical target for designing combination chemotherapy to overcome non-genetic drug resistance.

Antioxidative and antiproliferative activities of novel pyrido[1,2-a]benzimidazoles.

A series of pyrido[1,2-a]benzimidazoles has been designed, and novel examples are synthesized and evaluated for their potential antiproliferative activity against four human tumour cell lines-cervical (HeLa), colorectal (SW620), breast (MCF-7) and hepatocellular carcinoma (HepG2). In addition, their antioxidative potency has been evaluated by in vitro spectrophotometric assays. Preliminary structure-activity relationships among the synthesized compounds are discussed. Evaluation of their antioxidative capacity has shown that two compounds (25 and 26) possess promising reducing characteristics and free radical scavenging activity. Selective antiproliferative effect in the single-digit micromolar range was observed for compound 25 on MCF-7 [Formula: see text] and HeLa [Formula: see text] cell lines, comparable to the standards 5-fluorouracil and cisplatin. The combination of the radical scavenging activity and antiproliferative activity of compound 25 positions this compound as a potential lead candidate for further optimization.