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Fish bone fermented using Monascus purpureus (FBF) has total phenols and functional amino acids that contribute to its anti-oxidant and anti-inflammatory properties. Colorectal cancer, one of the most prevalent cancers and the third largest cause of death worldwide, has become a serious threat to global health. This study investigates the anti-cancer effects of FBF (1, 2.5 or 5 mg/mL) on the cell growth and molecular mechanism of HCT-116 cells. The HCT-116 cell treatment with 2.5 or 5 mg/mL of FBF for 24 h significantly decreased cell viability (p < 0.05). The S and G2/M phases significantly increased by 88–105% and 25–43%, respectively (p < 0.05). Additionally, FBF increased the mRNA expression of caspase 8 (38–77%), protein expression of caspase 3 (34–94%), poly (ADP-ribose) polymerase (PARP) (31–34%) and induced apoptosis (236–773%) of HCT-116 cells (p < 0.05). FBF also increased microtubule-associated protein 1B light chain 3 (LC3) (38–48%) and phosphoinositide 3 kinase class III (PI3K III) (32–53%) protein expression, thereby inducing autophagy (26–52%) of HCT-116 cells (p < 0.05). These results showed that FBF could inhibit HCT-116 cell growth by inducing S and G2/M phase arrest of the cell cycle, apoptosis and autophagy. Thus, FBF has the potential to treat colorectal cancer. [ABSTRACT FROM AUTHOR]

In this study, 2-benzyl-10a-(1H-pyrrol-2-yl)-2,3-dihydropyrazino[1,2-a]indole-1,4,10(10aH)-trione (DHPITO), a previously identified inhibitor against hepatocellular carcinoma cells, is shown to exert its cytotoxic effects by suppressing the proliferation and growth of CRC cells. An investigation of its molecular mechanism confirmed that the cytotoxic activity of DHPITO is mediated through the targeting of microtubules with the promotion of subsequent microtubule polymerisation. With its microtubule-stabilising ability, DHPITO also consistently arrested the cell cycle of the CRC cells at the G2/M phase by promoting the phosphorylation of histone 3 and the accumulation of EB1 at the cell equator, reduced the levels of CRC cell migration and invasion, and induced cellular apoptosis. Furthermore, the compound could suppress both tumour size and tumour weight in a CRC xenograft model without any obvious side effects. Taken together, the findings of the present study reveal the antiproliferative and antitumour mechanisms through which DHPITO exerts its activity, indicating its potential as a putative chemotherapeutic agent and lead compound with a novel structure. [ABSTRACT FROM AUTHOR]

Elevating cancer cell intracellular ROS production has been proven to be effective for cancer therapies. In this work, a series of 1,3-diphenylpyrimidine-2,4(1H,3H)-dione derivatives were designed and synthesized, of which the target compound XS23, N-(2,6-dioxo-1,3-di-m-tolyl-1,2,3,6-tetrahydropyrimidin-4-yl)-N-(3-morpholinopropyl)-2-phenylacetamide, exhibited excellent antitumor cell proliferative activity against multiple tumor cell lines. In the study of the antitumor mechanism of XS23, we confirmed that it can inhibit tumor cell migration and proliferation in a concentration-dependent manner in A375 cells. Besides, 5 μM of XS23 could induce 18% early cell apoptosis and 4.68% late cell apoptosis in A375 cells. XS23 can also dose-dependently and time-dependently increase cleaved the caspase-9 protein expression in A375 cells and increase the intracellular ROS level of A375 cells up to 175-fold compared with the negative control after 12 h, implying that XS23 can induce cancer cell apoptosis by elevating ROS production. [ABSTRACT FROM AUTHOR]

Background: Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour effects of T-96 against human Prostate cancer (CaP) cells and the possible underlying mechanisms have not been well studied. Results: In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Mechanistically, T-96 promoted the initiation of autophagy but inhibited autophagic flux by inducing ROS-mediated endoplasmic reticulum (ER) stress which subsequently activated the extrinsic apoptosis pathway in CaP cells. These findings implied that T-96-induced ER stress activated the caspase-dependent apoptosis pathway to inhibit proliferation of CaP cells. Moreover, we observed that T-96 enhances the sensitivity of CaP cells to the chemotherapeutic drug, cisplatin. Conclusions: Taken together, our data demonstrated that T-96 is a novel modulator of ER stress and autophagy, and has potential therapeutic applications against CaP in the clinic. [ABSTRACT FROM AUTHOR]

Summary: The synthesis of dTDP is unique because there is a requirement for thymidylate kinase (TMPK). All other dNDPs including dUDP are directly produced by ribonucleotide reductase (RNR). We report the binding of TMPK and RNR at sites of DNA damage. In tumor cells, when TMPK function is blocked, dUTP is incorporated during DNA double-strand break (DSB) repair. Disrupting RNR recruitment to damage sites or reducing the expression of the R2 subunit of RNR prevents the impairment of DNA repair by TMPK intervention, indicating that RNR contributes to dUTP incorporation during DSB repair. We identified a cell-permeable nontoxic inhibitor of TMPK that sensitizes tumor cells to doxorubicin in vitro and in vivo, suggesting its potential as a therapeutic option. [Copyright &y& Elsevier]

Compound K (20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol, CK), an intestinal bacterial metabolite of panaxoside, has been shown to inhibit tumour growth in a variety of tumours. However, the mechanisms involved are largely unknown. We use human gastric carcinoma cell lines BGC823, SGC7901 and human gastric carcinoma xenograft in nude mice as models to study the mechanisms of CK in gastric cancers. We found that CK significantly inhibits the viabilities of BGC823 and SGC7901 cells in dose- and time-dependent manners. CK-induced BGC823 and SGC7901 cells apoptosis and cell cycle arrest in G2 phase by up-regulation of p21 and down-regulation of cdc2 and cyclin B1. Further studies show that CK induces apoptosis in BGC823 and SGC7901 cells mainly through mitochondria-mediated internal pathway, and that CK induces the translocation of nuclear Bid to mitochondria. Finally, we found that CK effectively inhibited the tumour formation of SGC7901 cells in nude mice. Our studies show that CK can inhibit the viabilities and induce apoptosis of human gastric carcinoma cells via Bid-mediated mitochondrial pathway. [ABSTRACT FROM AUTHOR]

The development of cancer treatments requires continuous exploration and improvement, in which the discovery of new drugs for the treatment of cancer is still an important pathway. In this study, based on the molecular hybridization strategy, a new structural framework with an N-aryl-N'-arylmethylurea scaffold was designed, and 16 new target compounds were synthesized and evaluated for their antiproliferative activities against four different cancer cell lines A549, MCF7, HCT116, PC3, and human liver normal cell line HL7702. The results have shown seven compounds with 1-methylpiperidin-4-yl groups having excellent activities against all four cancer cell lines, and they exhibited scarcely any activities against HL7702. Among them, compound 9b and 9d showed greatly excellent activity against the four kinds of cells, and the IC50 for MCF7 and PC3 cell lines were even less than 3 μM. [ABSTRACT FROM AUTHOR]

To discover new antiproliferative agents with high efficacy and selectivity, a new series of 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea derivatives (7a–7t) were designed, synthesized and evaluated for their antiproliferative activity against A549, HCT-116 and PC-3 cancer cell lines in vitro. Most of the target compounds demonstrated significant antiproliferative effects on all the selective cancer cell lines. Among them, the target compound, 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio}phenyl}urea (7i) was identified to be the most active one against three cell lines, which was more potent than the positive control with an IC50 value of 1.53 ± 0.46, 1.11 ± 0.34 and 1.98 ± 1.27 μM, respectively. Further cellular mechanism studies confirmed that compound 7i could induce the apoptosis of A549 cells in a concentration-dependent manner and elucidated compound 7i arrests cell cycle at G1 phase by flow cytometry analysis. Herein, the studies suggested that the 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea skeleton might be regarded as new chemotypes for designing effective antiproliferative agents. [ABSTRACT FROM AUTHOR]

Cisplatin-based therapy is a traditional, clinical treatment for cancers, including lung cancer. In this study, we found that sequential therapy, i.e., cisplatin followed by fucoidan, reduced tumor volume in an LLC1-bearing C57BL/6 mouse model. Using a series of combined therapeutic experiments, we found that the inhibition rate of the sequential treatment (cisplatin→fucoidan) was 50-75%. However, the inhibition rate of the sequential treatment, with fucoidan pretreatment, was increased to 75-85%. Moreover, we found that the simultaneous administration of fucoidan and cisplatin synergistically inhibited lung cancer cell viability via inducing apoptotic responses, including upregulating cleaved caspase-3 and poly (ADP ribose) polymerase (PARP) expression. Mechanistically, we demonstrated that the fucoidan-induced, TLR4-mediated endoplasmic reticulum stress molecule CHOP promoted caspase-3 activation, which was further stimulated by the cisplatin-induced DNA damage responses, and CHOP shRNA eliminated fucoidan-induced caspase-3 cleavage but did not affect cisplatin-mediated apoptotic molecules. In addition, we observed an increasing number of clinical results that suggest combined cisplatin and fucoidan exerts a greater anti-tumorigenic effect in patients with lung cancer in Taiwan. Together, our current results support the potential of combined fucoidan and cisplatin treatment as an effective therapeutic strategy in lung cancer. [ABSTRACT FROM AUTHOR]

A sulfated 1,4-β -d- galactoglucan ( B86-III ) with 1,6-branches was isolated and identified from Antrodia cinnamomea . The repeating unit of B86-III was proposed based on one-dimensional 1D ( 1 H, 13 C and DEPT-135) and 2D (DQF-COSY, TOCSY, HSQC and HMBC) NMR spectra. The conformation of the sugars was hypothesized to be a rare boat form instead of a 4 C 1 chair form. The sulfate substitutions were suggested to be on the C-2 and C-3 positions, resulting in the following structure: B86-III inhibited the viability of H1975 lung cancer cells via cell apoptosis, including the activation of caspase 3 and PARP. Transforming growth factor β receptor (TGFR) and its downstream signaling FAK and Slug are involved in lung tumorigenesis. B86-III downregulated TGFR I protein levels and inhibited FAK phosphorylation, resulting in inhibition of Slug expression and migration. This study is the first to characterize sulfated polysaccharides with a rare boat-form conformation and identify the mechanism of inhibition lung cancer cell. [ABSTRACT FROM AUTHOR]

[Display omitted] Auristatins-glucuronide conjugates designed targeting the β-Glucuronidase in tumor microenvironment were synthesized and evaluated on stabilities, the release of auristatins and the antitumor activities in this study. Conjugates 20 and 21 showed remarkable stabilities in phosphate buffer and bovine serum solution, and excellent selectivity between the in vitro antiproliferative activities against β-glucuronidase pretreated and untreated cancer cells (IC 50 = 5.7 nM ∼ 9.7 nM, IC 50 (-Enz) > 1 μM). Furthermore, conjugate 20 showed potent antitumor efficacy in HCT-116 xenograft mouse model without inducing side effects. [ABSTRACT FROM AUTHOR]

The constitutive activation of ERK1/2 (RAF-MEK-ERK) signaling pathway has been widely observed in many types of tumors, and the blockade of ERK1/2 signaling pathway has been proved to reduce tumor growth. Therefore, ERK1/2 signaling pathway has become an interesting therapeutic target for cancer therapy. Despite the successful development of BRAF and MEK inhibitors in clinic treatment, resistance often appears to re-enhance ERK1/2 signaling. Here we report the design, synthesis, biological activity of a series of novel pyrido[2,3- d ]pyrimidine-2,4(1 H ,3 H)-dione derivatives based on compound 1. Among them, the target compound N -(3-chlorophenyl)-2-((1,3-dimethyl-7-(4-methylpiperazin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)amino)acetamide (14m) exhibited excellent antiproliferative activity towards MCF-7, A375, SK-MEL-2 and SK-HEP-1 cells, with low cytotoxicity in C28/I2 cells. Tumor spheroid assay demonstrated the superior potency of 14m in inhibiting the growth of SK-HEP-1 spheroidal models. The mechanism of 14m to induce cancer cell death was shown to suppress cell migrations, induce cell apoptosis, decrease the levels of phosphorylated ERK and MEK in a dose-dependent manner and increase ROS production. [Display omitted] • Novel pyrido[2,3- d ]pyrimidine-2,4(1 H ,3 H)-dione derivatives were discovered as anticancer agents. • Compound 14m displayed excellent antiproliferative activity against multi cancer cell lines. • Compound 14m blocked the phosphorylation of ERK and MEK in a dose-dependent manner. • Compound 14m can induce cell apoptosis by increasing ROS production. [ABSTRACT FROM AUTHOR]

Abstract: We studied potential interactions between the endoplasmic reticulum (ER) stress response and the MEK/ERK pathway. Induction of ER stress did not trigger significant apoptosis, but caused rapid activation of ERK1/2 in gastric cancer cells. Inhibition of MEK enhanced ER stress-induced apoptosis via a caspase-dependent, mitochondria-mediated mechanism. This was associated with blockage of ER stress-mediated up-regulation of GRP78. The latter appeared to be critical in antagonizing the apoptosis-inducing potential of ER stress. Thus, activation of MEK/ERK by ER stress is necessary for induction of GRP78 that protects against apoptosis in gastric cancer cells submitted to ER stress. [Copyright &y& Elsevier]

Docking model of 4e in the active site of ERα (3ERT). • A novel series of benzofuran derivatives were designed and synthesized through structural modification of raloxifene. • The benzofuran derivatives were evaluated for the anticancer activity in vitro against breast cancer cell lines. • A target compound has exhibited excellent anti-oestrogen receptor-dependent breast cancer cell lines activities and low toxicity. A docking study of a novel series of benzofuran derivatives with ERα was conducted. In this study, we report the synthesis of a novel series of benzofuran derivatives and evaluation of their anticancer activity in vitro against MCF-7 human breast cancer cells, as well as their potential toxicity to ER-independent MDA-MB-231 breast cancer cells, human renal epithelial HEK-293 cells, and human immortal keratinocytes (HaCaT cells) by using the MTT colorimetric assay. The screening results indicated that the target compounds exhibited anti-breast cancer activity. The target compound 2-benzoyl-3-methyl-6-[2-(morpholin-4-yl)ethoxy]benzofuran hydrochloride (4e) exhibited excellent activity against anti-oestrogen receptor-dependent breast cancer cells and low toxicity. The preliminary structure-activity relationships of the target benzofuran derivatives have been summarised. In conclusion, the novel benzofuran scaffold may be a promising lead for the development of potential oestrogen receptor inhibitors. [ABSTRACT FROM AUTHOR]