• BMB Reports
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• 제51권5호
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• pp.219-224
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• 2018

Necroptosis is an emerging form of programmed cell death occurring via active and well-regulated necrosis, distinct from apoptosis morphologically, and biochemically. Necroptosis is mainly unmasked when apoptosis is compromised in response to tumor necrosis factor alpha. Unlike apoptotic cells, which are cleared by macrophages or neighboring cells, necrotic cells release danger signals, triggering inflammation, and exacerbating tissue damage. Evidence increasingly suggests that programmed necrosis is not only associated with pathophysiology of disease, but also induces innate immune response to viral infection. Therefore, necroptotic cell death plays both physiological and pathological roles. Physiologically, necroptosis induce an innate immune response as well as premature assembly of viral particles in cells infected with virus that abrogates host apoptotic machinery. On the other hand, necroptosis per se is detrimental, causing various diseases such as sepsis, neurodegenerative diseases and ischemic reperfusion injury. This review discusses the signaling pathways leading to necroptosis, associated necroptotic proteins with target-specific inhibitors and diseases involved. Several studies currently focus on protective approaches to inhibiting necroptotic cell death. In cancer biology, however, anticancer drug resistance severely hampers the efficacy of chemotherapy based on apoptosis. Pharmacological switch of cell death finds therapeutic application in drug- resistant cancers. Therefore, the possible clinical role of necroptosis in cancer control will be discussed in brief.

• Asian Pacific Journal of Cancer Prevention
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• 제14권8호
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• pp.4615-4619
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• 2013

Background: Artesunate, extracted from Artemisia annua, has been proven to have anti-cancer potential. Allicin, diallyl thiosulfinate, the main biologically active compound derived from garlic, is also of interest in cancer treatment research. This object of this report was to document synergistic effects of artesunate combined with allicin on osteosarcoma cell lines in vitro and in vivo. Methods: After treatment with artesunate and allicin at various concentrations, the viability of osteosarcoma cells was analyzed by MTT method, with assessment of invasion and motility, colony formation and apoptosis. Western Blotting was performed to determine the expression of caspase-3/9, and activity was also detected after drug treatment. Moreover, in a nude mouse model established with orthotopic xenograft tumors, tumor weight and volume were monitored after drug administration via the intraperitoneal (i.p.) route. Results: The viability of osteosarcoma cells in the combination group was significantly decreased in a concentration and time dependent manner; moreover, invasion, motility and colony formation ability were significantly suppressed and the apoptotic rate was significantly increased through caspase-3/9 expression and activity enhancement in the combination group. Furthermore, suppression of tumor growth was evident in vivo. Conclusion: Our results indicated that artesunate and allicin in combination exert synergistic effects on osteosarcoma cell proliferation and apoptosis.

• Environmental Analysis Health and Toxicology
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• 제13권3_4호
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• pp.87-94
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• 1998

The use of cisplatin is limited by severe side effects such as renal toxicity. Our platinum-base drug discovery is aimed at developing drugs capable of diminishing toxicity and improving antitumor activity. We synthesized new Pt (II) complex analogue [Pt (cis-DACH)(DPPP)]. 2NO$_3$ (PC) containing cis-1,2-diaminocyclohexane as a carrier ligand and 1,3-bis(diphenylphosphino) propane as a leaving group. Furthermore, nitrate was added to improved the solubility. In this study, its structure was determined and its antitumor activity against SKOV-3 and NIH-OVCAR-3 human ovarian adenocarcinoma, and in vitro cytotoxicity was determined against primary cultured rabbit kidney proximal tubular and renal cortical cells of human kidney using colorimetric MTT assay. PC demonstrated acceptable antitumor activity against SKOV-3 and NIH-OVCAR-3 human ovarian adenocarcinoma and significant activity as compared with that of cisplatin. The toxicity of PC was found quite less than that of cisplatin using MTT and $^3$H-thymidine uptake tests in rabbit proximal tubular cells and human kidney cortical cells. PC was used for human cortical tissue in 7 weeks hitoculture by the glucose-consumption tests. We determined that the new platinum drug has lower nephrotoxicity than cisplatin. Based on these results, this novel platinum (II) complex compound (PC) represent a valuable lead in the development of a new anticancer chemotherapeutic agent capable of improving antitumor activity and low nephrotoxicity.

• Advances in Traditional Medicine
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• 제4권1호
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• pp.22-27
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• 2004

Cisplatin is a highly effective and extensively used anticancer drug. Higher doses of cisplatin manifest acute nephrotoxicity and this is one of the limiting factors of this drug in cancer chemotherapy. The effect of the oyster mushroom extract to ameliorate cisplatin ( cis platinum (II) diammine dichloride) induced nephrotoxicity and restoration of antioxidant defence system in mice was investigated. The investigations showed that prior administration of methanolic extract of Pleurotus florida at a dose of 500 and 1000mg/Kg body weight significantly reduced elevated serum creatinine and urea levels and increased superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities in the kidney, consequent to cisplatin treatment, in a dose dependent manner. The extract restored the decreased reduced glutathione (GSH) activity and increased malondialdehyde (MDA) level due to cisplatin administration. The results thus indicated that oyster mushroom extract rendered significant protection against cisplatin induced nephrotoxicity and depletion of antioxidant defence system in a dose dependent manner. Since oyster mushrooms are excellently edible and non-toxic, the finding reported here is of significant use in cancer chemotherapy.

• 방사선산업학회지
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• 제10권4호
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• pp.199-204
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• 2016

The dependence of cell survival on exposure dose and the duration of the liquid-holding recovery (LHR) was obtained for diploid yeast cells irradiated with ionizing radiation of different linear energy transfer (LET) and recovering from radiation damage without and with various concentrations of cisplatin - the most widely used anticancer drug. The ability of yeast cells to recover from radiation damage was less effective after cell exposure to high-LET radiation, when cells were irradiated without drug. The increase in cisplatin concentration resulted in the disappearance of this difference whereas the fraction of irreversible damage was permanently enlarged independently of radiation quality. The probability of cell recovery was shown to be constant for various conditions of irradiation and recovery. A new mechanism of cisplatin action was suggested according with which the inhibition of cell recovery after exposure to ionizing radiations was completely explained by the production of irreversible damage.

• Archives of Pharmacal Research
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• 제27권7호
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• pp.693-712
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• 2004

The rats with protein-calorie malnutrition (PCM, 5％ casein diet for a period of 4-week) were reported to exhibit 60 and 80％ suppression in the hepatic microsomal cytochrome P450 (CYP) 1 A2 and CYP2C11 levels, respectively, and 40-50％ decreases in CYP2E1 and CYP3A 1/2 levels compared to control (23％ casein diet for a period of 4-week) based on Western blot analysis. In addition, Northern blot analysis showed that CYP1 A2, CYP2E1, CYP2C11, and CYP3A1/2 mRNAs decreased in the state of PCM as well. Hence, pharmacokinetic changes of the drugs in rats with PCM [especially the area under the plasma concentration-time curve from time zero to time infinity (AUC) changes of metabolite(s)] reported from literatures were tried to explain in terms of CYP isozyme changes in the rats. Otherwise, the time-averaged nonrenal clearance ($CL_{NR}$) of parent drug was compared. Pharmacokinetic changes of the drugs in other types of malnutritional state, such as kwashiorkor and marasmus, in both human and animal models were also compared. The drugs reviewed are as follows： diuretics, antibiotics, anticancer agents, antiepileptics, antiarrythmics, analgesics, xanthines, antimalarials, and miscellaneous.

• Journal of Microbiology and Biotechnology
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• 제32권6호
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• pp.718-729
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• 2022

Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy with poor prognosis. Here, due to the necessity for exploring potential therapies against ESCC, we obtained the gene expression data on ESCC from the TCGA and GEO databases. Venn diagram analysis was applied to identify common targets. The protein-protein interaction network was constructed by Cytoscape software, and the hub targets were extracted from the network via cytoHubba. The potential hub nodes as drug targets were found by pharmacophore-based virtual screening and molecular modeling, and the antitumor activity was evaluated through in vitro studies. A total of 364 differentially expressed genes (DEGs) in ESCC were identified. Pathway enrichment analyses suggested that most DEGs were mainly involved in the cell cycle. Three hub targets were retrieved, including CENPF, CCNA2 (cyclin A), and CCNB1 (cyclin B1), which were highly expressed in esophageal cancer and associated with prognosis. Moreover, amentoflavone, a promising drug candidate found by pharmacophore-based virtual screening, showed antiproliferative and proapoptotic effects and induced G1 in esophageal squamous carcinoma cells. Taken together, our findings suggested that amentoflavone could be a potential cell cycle inhibitor targeting cyclin B1, and is therefore expected to serve as a great therapeutic agent for treating esophageal squamous cell carcinoma.

• The Korean Journal of Physiology and Pharmacology
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• 제27권5호
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• pp.471-479
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• 2023

Disulfiram (DSF), a medication for alcoholism, has recently been used as a repurposing drug owing to its anticancer effects. Despite the crucial role of dendritic cells (DCs) in immune homeostasis and cancer therapy, the effects of DSF on the survival and function of DCs have not yet been studied. Therefore, we treated bone marrow-derived DCs with DSF and lipopolysaccharide (LPS) and performed various analyses. DCs are resistant to DSF and less cytotoxic than bone marrow cells and spleen cells. The viability and metabolic activity of DCs hardly decreased after treatment with DSF in the absence or presence of LPS. DSF did not alter the expression of surface markers (MHC II, CD86, CD40, and CD54), antigen uptake capability, or the antigen-presenting ability of LPS-treated DCs. DSF decreased the production of interleukin (IL)-12/23 (p40), but not IL-6 or tumor necrosis factor-α, in LPS-treated DCs. We considered the granulocyte-macrophage colony-stimulating factor (GM-CSF) as a factor to make DCs resistant to DSF-induced cytotoxicity. The resistance of DCs to DSF decreased when GM-CSF was not given or its signaling was inhibited. Also, GM-CSF upregulated the expression of a transcription factor XBP-1 which is essential for DCs' survival. This study demonstrated for the first time that DSF did not alter the function of DCs, had low cytotoxicity, and induced differential cytokine production.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제28권2호
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• pp.95-110
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• 2006

The treatment for oral and maxillofacial carcinoma with chemotherapeutic agents is evaluated by many effective methods to reduce the tumor mass and cancer cell proliferation. However these chemotherapy have many serious side effects, such as bone marrow suppression, renal toxicity, G-I troubles. Therefore a possible approach to develop a clinically applicable chemotherapeutic agent is to screen anticancer activity of Taxol which is known to have very little side effect and have been used to breast cancer and ovarian carcinoma. Taxol is a new anti-microtubular anti-cancer agent extracted from the bark of the Pacific yew, Taxus brevifolia. Paclitaxel(Taxol) acts by promoting tubulin polymerization and over stabilizing microtubules agianst depolymerization. Despite the constant improvements of methods of the cancer treatment especially chemotherapy, the rate of cancer metastasis and recurrent are not decreased. Thus the investigation of new drug which have very little side effect and a possible clinically application continues to be a high priority. Considering that the Taxol have shown very effective chemotherapeutic agent with relatively low toxicity in many solid tumors, it deserves to evaluate its efficacy in oral squamous cell carcinoma. In this study, to investigate the in-vivo and in-vitro anti-cancer efficacy of Taxol in oral squamous cell carcinoma and lastly, the potency of Paclitaxel in the clinical application for oral cancer was evaluated. In vivo study, after HN22 cell line were xenografted in nude mice, the growth of tumor mass was observed, 3 mg/Kg taxol was injected intraperitoneally into nude mice containing tumor mass. The methods of these study were measurement of total volume of tumor mass, histopathologic study, immunohistochemical study, drug resistance assay, growth curve, MTT assay, flow cytometry, cDNA microarray in vivo and in vitro. The results were obtained as following. 1. The visual inspection of the experimental group showed that the volume of the tumor mass was slightly decreased but no significant difference with control group. 2. Ki-67 index was decreased at weeks 4 in experimental group. 3. Microscopic view of the xenografted tumor mass showed well differentiated squamous cell carcinoma and after Taxol injection, some necrotic tissue was seen weeks 4. 4. The growth curve of the tumor cells were decreased after 1day Taxol treatment. 5. According to the MTT assay, HN22 cell line showed relative drug resistancy above $5\;{\mu}g/ml$ concentrations of Taxol. 6. In drug resistance assay, the decrease of cell counts was seen relatively according to concentration. 7. In Flow cytometry, G2M phase cell arrests were seen in low concentration of the Taxol, while S phase cell arrests were seen in high concentration of the Taxol. 8. Using cDNA microarray technique, variable gene expression of ANGPTL4, TXNRD1, FAS, RRAGA, CTGF, CYCLINEA, P19, DUSP5, CEBPG, BTG1 were detacted in the oral squamous cell carcinoma cell after taxol treatment. In this study paclitaxel is effective against oral squamous cell carcinoma cell lines in vitro, but week effect was observed in vivo. So we need continuous study about anticancer effect of taxol in vivo in oral squamous cell carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• 제16권14호
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• pp.6117-6121
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• 2015

Background: Most northeast Thai vegetables may play roles in human health by acting as antioxidant and anticancer agents. Recent study showed that Cratoxylum formosum subsp. pruniflorum (Kurz.) Gogel. (Teawdang) could inhibit growth of liver cancer cell lines. Cervical cancer, which has human papilloma virus as its main cause, is found at high incidence in Thailand. Due to increasing drug resistance, searches for potential anticancer compounds from natural source are required. Therefore, our purpose was to evaluate the cytotoxicity of Teawdang extracts in cervical cancer cell lines. Materials and Methods: Teawdang edible parts, purchased from Khon Kaen market during July-October 2013 was extracted with organic solvent. Phenolic profiles of crude hexane (CHE), ethyl acetate (CEE), methanol (CME) and water (CWE) extracts were performed by high performance liquid chromatographic (HPLC) techniques. Their cytotoxic effects on cervical cancer cells were investigated with HPV-non infected (C-33A) and HPV-infected (HeLa and SiHa) cell lines. Results: HPLC profiles showed that all crude extracts contained caffeine, ferulic acid and resveratrol. CME and CEE had high contents of gallic acid and quercetin. Catechin was found only in CWE. Cytotoxicity test showed that CEE had the lowest IC50 on HeLa ($143.18{\pm}13.35 {\mu}g/mL$) and SiHa cells ($106.45{\pm}15.73{\mu}g/mL$). C-33A cells were inhibited by CWE ($IC50=130.95{\pm}3.83{\mu}g/mL$). Conclusions: There were several phenolic compounds in Teawdang extracts which may have cytotoxic effects on cervical cancer cell lines. Investigation of these bioactive compounds as new sources of anticancer agents is recommended.