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Treatment of recurrent and metastatic cervical cancer remains a challenge, especially in developing countries, which lack efficient screening programs. In recent years, artemisinin and its derivatives, such as dihydroartemisinin (DHA), which were traditionally used as anti-malarial agent, have been shown to inhibit tumor growth with low toxicity to normal cells. In this study, we investigated mechanisms underlying the anti-tumor effect of DHA in cervical cancer. We evaluated the role of DHA on the expression of bcl-2 and Raf kinase inhibitor protein (RKIP), which is a suppressor of metastasis. The MTT assay was used to compare the proliferation of untreated and DHA-treated Hela and Caski cervical cancer cells. Flow cytometry was used to determine the percentage of cells at each stage of the cell cycle in untreated and DHA-treated cells. We used RT-PCR and western blots to determine the expression of bcl-2 and RKIP mRNA and proteins. We evaluated the effect of DHA treatment in nude mice bearing Hela or Caski tumors. DHA-treated cells showed a time- and dose-dependent inhibition of proliferation and a significant increase in apoptosis. The expression of RKIP was significantly upregulated and the expression of bcl-2 was significantly downregulated in DHA-treated cells compared with control cells. DHA treatment caused (1) a significant inhibition of tumor growth and (2) a significant increase in the apoptotic index in nude mice bearing Hela or Caski tumors. Our data suggest that DHA inhibits cervical cancer growth via upregulation of RKIP and downregulation of bcl-2.

Objective: The role of Ulinastatin in neuronal injury after cardiopulmonary resuscitation has not been elucidated. We aim to evaluate the effects of Ulinastatin on inflammation, oxidation, and neuronal injury in the cerebral cortex after cardiopulmonary resuscitation., Methods: Ventricular fibrillation was induced in 76 adult male Wistar rats for 6 min, after which cardiopulmonary resuscitation was initiated. After spontaneous circulation returned, the rats were split into two groups: the Ulinastatin 100,000 unit/kg group or the PBS-treated control group. Blood and cerebral cortex samples were obtained and compared at 2, 4, and 8 h after return of spontaneous circulation. The protein levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were assayed using an enzyme-linked immunosorbent assay, and mRNA levels were quantified via real-time polymerase chain reaction. Myeloperoxidase and Malondialdehyde were measured by spectrophotometry. The translocation of nuclear factor-κB p65 was assayed by Western blot. The viable and apoptotic neurons were detected by Nissl and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)., Results: Ulinastatin treatment decreased plasma levels of TNF-α and IL-6, expression of mRNA, and Myeloperoxidase and Malondialdehyde in the cerebral cortex. In addition, Ulinastatin attenuated the translocation of nuclear factor-κB p65 at 2, 4, and 8 hours after the return of spontaneous circulation. Ulinastatin increased the number of living neurons and decreased TUNEL-positive neuron numbers in the cortex at 72 h after the return of spontaneous circulation., Conclusions: Ulinastatin preserved neuronal survival and inhibited neuron apoptosis after the return of spontaneous circulation in Wistar rats via attenuation of the oxidative stress response and translocation of nuclear factor-κB p65 in the cortex. In addition, Ulinastatin decreased the production of TNF-α, IL-6, Myeloperoxidase, and Malondialdehyde.

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., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

It was recently shown that compound K (CK), an intestinal bacterial metabolite of ginseng saponin, exhibits antihepatocellular carcinoma (HCC) activity, and Bid is a potential drug target for HCC therapy. This paper reports a novel mechanism of CK-induced apoptosis of HCC cells via Bid-mediated mitochondrial pathway. CK dramatically inhibited HCC cells growth in concentration- and time-dependent manners, and a high dose of CK could induce HCC cell apoptotic cell death. Furthermore, the effective dose of CK potently attenuated the subcutaneous tumor growth and spontaneous HCC metastasis in vivo. At the molecular level, immunohistochemical staining revealed that Bid expression in subcutaneous tumor and liver metastasis tissues decreased dramatically in CK-treated groups compared to untreated controls, which also implies that Bid may play a critical role in the growth and progression of HCC. Further study shows that translocation of full-length Bid to the mitochondria from nuclei during cytotoxic apoptosis was associated with the release of cytochrome c from mitochondria, indicating that full-length Bid is sufficient for the activation of mitochondrial cell death pathways in response to CK treatment in HCC cells. Taken together, the results not only reveal a Bid-mediated mitochondrial pathway in HCC cells induced by CK but also suggest that CK may become a potential cytotoxic drug targeting Bid in the prevention and treatment of HCC.

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.

Although cisplatin has been shown to induce both apoptosis and necrosis in cancer cells, the potential interconnections between these modes of cell death induced by the drug remain unknown. We studied this phenomenon in gastric cancer cell lines and identified one cell line (SGC-7901) that underwent apoptosis, and another cell line (BGC-823) that primarily underwent nonapoptotic cell death, in response to cisplatin. Apoptosis in cisplatin-treated SGC-7901 cells seemed to be caspase dependent and was mediated, at least in part, by the BH3-only protein, Noxa. This was evidenced by the rapid upregulation of Noxa and inhibition of apoptosis by small interfering RNA knockdown of Noxa. Nonapoptotic cell death induced by cisplatin in BGC-823 cells was characterized by lack of DNA fragmentation, delayed externalization of phosphatidylserine, caspase independence, plasma membrane disruption, and intracellular vacuole formation, indicative of necrosis. Surprisingly, blockage of apoptosis induction by a general caspase inhibitor or by Noxa small interfering RNA in SGC-7901 failed to protect against cisplatin-induced cell death. Under such conditions, SGC-7901 cells displayed cellular features associated with necrosis. Cisplatin-induced apoptosis, thus, seems to precede necrosis when the apoptotic machinery is operative. When the apoptosis program is defective, necrotic cell death takes place as an alternative pathway leading to cell demise. Induction of different modes of cell death that are interrelated in the same cells by cisplatin has the potential to be exploited in formulating new adjuvant cancer therapies.

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]

Cervical cancer is one of the primary causes of cancer‑associated mortality worldwide. Due to the increasing incidence of cervical cancer, multiple treatment options are required. Initial responses to chemotherapy and surgical interventions are generally positive, however patients often experience relapse and tumor recurrence. Currently, the effects of cucurbitacins on different types of cancer are being investigated, as they exhibit a wide variety of bioactivities. The anticancer activity of the cucurbitacin 23,24‑dihydrocucurbitacin B against a panel of human cervical cancer cell lines was investigated in the current study. Cell viability was determined using an MTT assay and apoptosis was detected using DAPI staining. The proportion of apoptotic cells, cell cycle distribution, mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) levels were estimated using flow cytometry. Protein expression was determined using western blot analysis. The results of the current study indicated that 23,24‑dihydrocucurbitacin B inhibited the viability of human cervical cancer cell lines and had an IC50 of 40‑60 µM. However, its cytotoxic effects were much less pronounced in normal epithelial fr2 and HerEpiC cells, where it had an IC50 of 125 µM. The underlying mechanisms of this were further studied and the results demonstrated that 23,24‑dihydrocucurbitacin B induced apoptosis in HeLa cells and caused ROS‑mediated shifts in the ΔΨm. Additionally, it caused the cell cycle arrest of HeLa cells at the G2/M checkpoint. The phosphoinositide 3 kinase/protein kinase B/mechanistic target of rampamycin (PI3K/AKT/mTOR) cascade may serve an important role in cancer tumorigenesis, progression and resistance to chemotherapy. The results indicated that 23,24‑dihydrocucurbitacin B significantly decreased the expression of important proteins in the PI3K/Akt/mTOR cascade. Taken together, these results suggest that 23,24‑dihydrocucurbitacin B may be novel method of treating cervical cancer. [ABSTRACT FROM AUTHOR]

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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]

Naturally occurring compounds are reported as effective candidates for prevention and treatment of various cancers. Breviscapine (BVP) is a mixture of flavonoid glycosides, derived from the Chinese herbs. Previous researches have indicated that BVP has comprehensive pharmacological functions. However, little is known about whether BVP has preventive effects on human prostate cancer. Here, we attempted to explore if BVP inhibits human prostate cancer in vitro and in vivo in a comprehensive manner. We found that BVP triggered cytotoxicity in prostate cancer cell lines dose-dependently. BVP-induced DNA damage caused the cell cycle arrest and apoptosis and further induced cell death. High expression of MCM-7 was reduced in BVP-treated cancer cells and tumor tissues, and also the DNA damage response marker of γH2AX is down-regulated by BVP, associated with MCM-7 expression through regulating retinoblastoma protein (Rb) and checkpoint control proteins expression. Additionally, BVP induced apoptotic response in prostate cancer cells and tumors via activating Caspase-3 and PARP. In vivo studies indicated that BVP impeded tumor growth in xenograft animal models. In conclusion, our data indicates that breviscapine (BVP) can be further explored for its potential, which might be used in human prostate cancer therapeutics. [ABSTRACT FROM AUTHOR]