Anti-angiogenic gene therapy for hepatocellular carcinoma mediated by microbubble-enhanced ultrasound exposure: An in vivo experimental study

Objective: The aim of this study was to assess the effect of anti-angiogenic gene therapy for hepatocelluar carcinoma (HCC) treated by microbubble-enhanced ultrasound exposure.

Methods: Forty C57BL/6J female mice were inoculated s.c. with Hepa1-6 tumor cell line. Herpes simplex virus thymidine kinase under the control of kinase domain-containing receptor (KDR, angiogenic growth factor's corresponding receptor) promoter was used. Plasmid DNA with or without microbubble contrast agent of SonoVue? was i.v. injected. Ultrasound (1 MHz, 2 W/cm², 5 min) was delivered to hepatic carcinomas in mice. The KDR-tk gene transfer was followed by ganciclovir (GCV) injection for 10 days and then the diameters of tumors were measured every 4 days till 28 days. The survivals of tumor-bearing mice were observed. PCR analysis and immunohistochemistry measurements revealed expression of the transfected gene. Transferase-mediated dUTP nick end labeling staining was used to detect apoptotic cells.

Results: Compared with the group treated by ultrasound alone, KDR-tk gene treatment treated by ultrasound combined with SonoVue restrained tumor growth and increased survival time of tumor-bearing mice; microvessel density in group mediated by ultrasound and SonoVue was significantly lower than that in group ultrasound alone (12.3 ± 1.4 vs. 27.4 ± 3.2, P < 0.05). An apoptosis index increased in the group treated by ultrasound and SonoVue compared with the group treated by ultrasound alone (25 ± 3.6 vs. 36 ± 3.8, P < 0.05), whereas there was no significant difference between group mediated by SonoVue alone and group phosphate-buffered saline alone (17 ± 1.8 vs. 14 ± 1.2, P>0.05).

Conclusions: Gene therapy mediated by ultrasound exposure enhanced by a microbubble contrast agent may become a new treatment option for persistent HCC.     

Genistein induces activation of the mitochondrial apoptosis pathway by inhibiting phosphorylation of Akt in colorectal cancer cells

Context: Genistein inhibits the proliferation and induces apoptosis of colorectal cancer cells; however, the underling molecular mechanisms remain to be determined.

Aim: The aim of this study was to investigate whether genistein reduces cell viability by suppressing the phosphorylation of AKT and activating the mitochondrial apoptosis pathway in colorectal cancer cells.

Materials and methods: The anti-proliferative effects of genistein (0, 25, 50, and 100?μM) on HCT-116 and LoVo cells were assessed using MTT assay. Genistein-induced apoptosis was measured by Hoechst 33258 staining and flow cytometry. The mRNA level of Bax was detected by real-time PCR. The protein levels of Bax, total Akt, and phosphorylated Akt were assessed by western blot.

Results: The IC₅₀ values of genistein were 690, 135, and 61?μM in HCT-116 cells and 204, 135, and 93?μM in LoVo cells after treatment for 24, 48, and 72?h, respectively. After treatment with different concentrations of genistein (0, 25, 50, and 100?μM) for 48?h, the early apoptotic cells in HCT-116 increased from 1.99%?±?0.55% to 6.78%?±?2.12%, 23.16%?±?3.87%, and 36.99%?±?3.76%, respectively. The same concentrations of genistein increased the early apoptotic cells in LoVo from 2.56%?±?1.42% to 3.21%?±?1.52%, 18.22%?±?3.56%, and 23.56%?±?3.02%, respectively. Moreover, genistein increased the mRNA and protein levels of Bax, while it inhibited the phosphorylation of Akt in HCT-116 cells.

Conclusion: Genistein inhibited cell proliferation and induced apoptosis of colorectal cancer cells. Genistein induced the mitochondrial pathway of apoptosis in HCT-116 cells by inhibiting phosphorylation of Akt.     

Syringic acid from Tamarix aucheriana possesses antimitogenic and chemo-sensitizing activities in human colorectal cancer cells

Abstract

Context: For its variety of biological activities, Tamarix aucheriana (Decne.) Baum. (Tamaricaceae) has an extensive history as a traditional Arab medicine.

Objectives: Antimitogenic and chemo-sensitizing activities of syringic acid (SA) were studied against human colorectal cancer.

Materials and methods: Chromatographic and spectral data were used for the isolation and identification of SA. MTT, flow cytometry, in vitro invasion and angiogenesis assays, fluoremetry, ELISA and Real Time qPCR were used to test antimitogenic and chemo-sensitizing activities of SA, cell cycle, apoptosis, proteasome and NFκB-DNA-binding activities, cancer cell invasion and angiogenesis, and expression of cell cycle/apoptosis-related genes.

Results: SA showed a time- and dose-dependent (IC₅₀?=?0.95–1.2?mg?mL^?1) antimitogenic effect against cancer cells with little cytotoxicity on normal fibroblasts (≤20%). SA-altered cell cycle (S/G2-M or G1/G2-M phases) in a time-dependent manner, induced apoptosis, inhibited DNA-binding activity of NFκB (p?≤?0.0001), chymotrypsin-like/PGPH (peptidyl-glutamyl peptide-hydrolyzing) (p?≤?0.0001) and the trypsin-like (p?≤?0.002) activities of 26S proteasome and angiogenesis. SA also differentially sensitized cancer cells to standard chemotherapies with a marked increase in their sensitivity to camptothecin (500-fold), 5FU (20?000-fold), doxorubicin (210-fold), taxol (3134-fold), vinblastine (1000-fold), vincristine (130-fold) and amsacrine (107-fold) compared to standard drugs alone.

Discussion: SA exerted its chemotherapeutic and chemo-sensitizing effects through an array of mechanisms including cell-cycle arrest, apoptosis induction, inhibition of cell proliferation, cell migration, angiogenesis, NFκB DNA-binding and proteasome activities.

Conclusion: These results demonstrate the potential of SA as an antimitogenic and chemo-sensitizing agent for human colorectal cancer.     

Plumbagin induces apoptosis,cell cycle arrest,and inhibits protein synthesis in LoVo colon cancer cells: A proteomic analysis

Extracted from the roots of Plumbago zeylanica L., plumbagin is a natural naphthoquinone with potential as an anticancer compound. However, no studies have investigated its impact on LoVo (colon cancer) cells, and the specific mechanisms by which plumbagin exerts its anticancer effects remain to be established. The anticancer potential of plumbagin against LoVo cells was evaluated using a battery of assays, including MTT assay, clone formation assay, transwell chamber invasion assay, and wound-curing assay. Cell cycle analysis and cell apoptosis analysis were conducted to break down the anticancer impact of plumbagin on LoVo cells. A label-free proteomics technology was employed to investigate alterations in protein expression in LoVo cells treated with plumbagin. Our investigation indicated that plumbagin markedly inhibited the LoVo cells proliferation, and induced the apoptosis in LoVo cells, simultaneously induced G0/G1 phase cell cycle arrest. The LC-MS/MS proteomics assay revealed 78 proteins that were differentially expressed upon treatment with plumbagin. Bioinformatics and functional analyses indicated that these proteins were predominantly involved in protein synthesis and translation. Our findings revealed that multiple mechanisms are involved in the anticancer activity of plumbagin against LoVo cells, resulting in decreased cell viability. Proteomic analysis suggests that plumbagin may impede protein synthesis by reducing the expression of eukaryotic initiation factors. Our findings demonstrate that plumbagin exerts its anticancer activity against LoVo cells through multiple mechanisms, including inhibition of cell proliferation, induction of apoptosis, cell cycle arrest, and disruption of protein synthesis. These results provide new insights into the therapeutic potential of plumbagin for colon cancer treatment.     

HMGA1 silencing reduces stemness and temozolomide resistance in glioblastoma stem cells

Objective: Glioblastoma multiforme (GBM) develops from a small subpopulation of stem-like cells, which are endowed with the ability to self-renew, proliferate and give rise to progeny of multiple neuroepithelial lineages. These cells are resistant to conventional chemo- and radiotherapy and are hence also responsible for tumor recurrence.

HMGA1 overexpression has been shown to correlate with proliferation, invasion, and angiogenesis of GBMs and to affect self-renewal of cancer stem cells from colon cancer. The role of HMGA1 in GBM tumor stem cells is not completely understood.

Research design and methods: We have investigated the role of HMGA1 in brain tumor stem cell (BTSC) self-renewal, stemness and resistance to temozolomide by shRNA- mediated HMGA1 silencing.

Results: We first report that HMGA1 is overexpressed in a subset of BTSC lines from human GBMs. Then, we show that HMGA1 knockdown reduces self-renewal, sphere forming efficiency and stemness, and sensitizes BTSCs to temozolomide. Interestingly, HMGA1 silencing also leads to reduced tumor initiation ability in vivo.

Conclusions: These results demonstrate a pivotal role of HMGA1 in cancer stem cell gliomagenesis and endorse HMGA1 as a suitable target for CSC-specific GBM therapy.     

Inhibition of invasion and metastasis of human liver cancer HCCLM3 cells by portulacerebroside A

Abstract

Context: Portulacerebroside A (PCA) is a novel cerebroside compound isolated from Portulaca oleracea L. (Portulacaceae), an edible and medicinal plant distributed in the temperate and tropical zones worldwide.

Objective: This study investigates the effects of PCA in human liver cancer HCCLM3 cells on metastasis and invasion.

Materials and methods: After the cells were treated with PCA (2.5, 5, and 10?μg/ml) for 6, 12, 24, or 48?h, adhesion, transwell invasion, and scratch tests were conducted and cell functions were evaluated. Western blot and FQ-RT-PCR assays explored the mechanism of PCA-inhibited invasion and metastasis in the cells.

Results: The adhesion rate of the cells was suppressed at 0.5?h (79.4?±?1.0, 68.7?±?1.3, and 58.1?±?1.3%, versus 100?±?1.5% in the control), 1?h (78.2?±?1.2, 70.9?±?1.6, and 55.4?±?1.9%, versus 100?±?1.2% in the control), and 1.5?h (71.6?±?1.1, 62.3?±?0.9, and 50.4?±?0.9%, versus 100?±?1.1% in the control). The 24?h invasion ability was decreased (356.6?±?11.2, 204.0?±?17.6, and 113.0?±?9.5%, versus 443.6?±?15.4% in the control). The migration capability was also restrained by PCA for 24?h (324.8?±?25.4, 250.4?±?21.0, and 126.3?±?10.1, versus 381.6?±?30.6 in the control) and 48?h (470.3?±?34.3, 404.0?±?19.7, and 201.0?±?15.4, versus 752.0?±?63.6 in the control). There was an increase in the mRNA and protein expression levels of TIMP-2 and nm23-H1, inhibition in the mRNA expression of MTA1, MMP-2, and MMP-9, and suppression in the protein expression of MTA1, RhoA, Rac1/Cdc42, MMP-2, but not RhoC and MMP-9.

Conclusion: PCA suppresses the invasion and metastasis of HCCLM3 cells possibly by modulation of the mRNA and protein expression of related parameters. This is the first study to reveal a new potential therapeutic application of PCA in antimetastatic therapy for liver cancer.     

Ethyl acetate extract from Glycosmis parva leaf induces apoptosis and cell-cycle arrest by decreasing expression of COX-2 and altering BCL-2 family gene expression in human colorectal cancer HT-29 cells

Abstract

Context: Glycosmis parva Craib (Rutaceae) is reported to have cytotoxic and anti-inflammatory activities by decreasing COX-2 expression.

Objective: To investigate the effect of G. parva on human colorectal cancer cells expressing COX-2, HT-29 cells.

Materials and methods: HT-29 cells were treated with ethyl acetate extract from the leaves of G. parva (GPE 6.25–100?µg/ml) for 24–72?h. Cell viability was evaluated by the resuzurin reduction assay. An apoptotic study was performed using annexinV/FITC-PI staining. The cell-cycle pattern was investigated by PI staining. The expression of BCL-2 family genes was analyzed by quantitative RT-PCR and expression of cyclins and COX-2 were done by RT-PCR.

Results: GPE at 6.25–100?µg/ml reduced HT-29 cell viability with IC₅₀ values of 69.49, 55.89, and 48.94?µg/ml at 24, 48, and 72?h, respectively. HT-29 apoptosis was induced by 18.23% at 100?µg/ml. Cells in S phase decreased by 5.22% and 13.28% at 50 and 100?µg/ml, respectively, causing G0/G1 (10.6% at 50?µg/ml) and G2/M (15.67% at 100?µg/ml) accumulation. GPE at 50?µg/ml downregulated cyclin A (11.46%), cyclin E (17.98%), BCL-2 (0.32-fold), and COX-2 (29.06%) expression with an increased BAK expression (1.79-fold).

Discussion and conclusion: GPE reduced HT-29 cell viability, inhibited cell proliferation, induced apoptosis, and arrested the cell cycle. Underlying mechanisms may involve decreases in COX-2, cyclin A, and cyclin E expression in addition to changes in BCL-2 family gene expression. Fundamental knowledge of GPE anticancer effects found in this study could lead to future use of this compound for colorectal cancer treatment.     

RhoGDI2 as a therapeutic target in cancer

Importance of the field: Rho GDP dissociation inhibitor 2 (RhoGDI2) has been identified as a regulator of Rho GTPases that play important roles in the development of numerous aspects of the malignant phenotype, including cell cycle progression, resistance to apoptotic stimuli, neovascularization, tumor cell motility, invasiveness, and metastasis. Although RhoGDI2 has been known to be expressed only in hematopoietic tissues, recent studies suggest that this protein is also aberrantly expressed in several human cancers and contributes to aggressive phenotypes, such as invasion and metastasis. Hence, RhoGDI2 appears to be a target of interest for therapeutic manipulation.

Areas covered in this review: Here, we summarize the role of RhoGDI2 in human cancers, specifically metastasis-related processes, and discuss its potential as a therapeutic target.

What the reader will gain: RhoGDI2 modulates the invasiveness and metastatic ability of cancer cells through regulation of Rac1 activity.

Take home message: RhoGDI2 may be a useful marker for tumor progression in human cancers, and interruption of the RhoGDI2-mediated cancer cell invasion and metastasis by an interfacial inhibitor may be a powerful therapeutic approach to cancer.     

Phospholipids-based microbubbles sonoporation pore size and reseal of cell membrane cultured in vitro

Objective: To investigate phospholipids-based microbubbles induced sonoporation and cell membrane reseal in vitro under various conditions.

Methods: A breast cancer cell line SK-BR-3 was used to investigate ultrasonic sonoporation under various conditions. Atomic force microscopy (AFM) scanning techniques were employed to observe the change of membrane pores.

Results: Normal SK-BR-3 cells membrane pores were evenly distributed and less than 1 μm. After ultrasound exposure, membrane pores were enlarged at different degree depending on ultrasound exposure durations, filling gas species and microbubble suspension concentration. With microbubble suspension concentration being increased to 5% or ultrasound exposure reached 30 s, membrane pores in fluorocarbon (C₃F₈ or SF₆)-filled microbubble groups exceeded 1 μm, which were significantly larger than that of air-filled microbubble group. Membrane pores were about 2–3 μm under ultrasound 60 s with 5% fluorocarbon-filled microbubble suspension. After 24 h of incubation, most of the enlarged membrane pores could reseal to normal size, which corresponded to cell viability.

Conclusions: Membrane pores can be obviously enlarged by ultrasonic sonoporation of fluorocarbon-filled microbubbles, whose reseal time depended on ultrasound exposure duration and microbubble suspension concentration.     

Cost implications of post-surgical morbidity following blood transfusion in cancer patients undergoing elective colorectal resection: an evaluation in the US hospital setting

ABSTRACT

Objective: To estimate the cost implications of blood transfusions and related surgical site infections (SSIs) in cancer patients undergoing elective colorectal resection in the hospital setting in the United States (US).

Study design: A modelling study was performed from the perspective of the hospital sector, based on published clinical outcomes from a study in Taiwan involving 2809 cancer patients who underwent elective colorectal resection using laparotomy and American treatment patterns.

Methods: Data on resource use were retrieved from published literature and from two American hospital centres specialising in colorectal cancer management. Decision analytical modelling was used to estimate the treatment costs and consequences of managing patients undergoing elective colorectal resection with and without blood transfusions.

Results: The expected treatment costs of managing patients who required and did not require a blood transfusion were estimated to be $19?869 (95% CI: 15?797; 23?150) and $14?586 (95% CI: 14?263; 14?886) per patient respectively. Expected treatment costs for those patients transfused with 1–3?units and > 3?units of blood were estimated to be $17?449 and $22?588 per patient respectively.

Conclusion: This is one of the first studies to specifically address the cost implications of post-surgical morbidity following colorectal resection in cancer patients. The cost of managing cancer patients undergoing elective colorectal resection who require a blood transfusion is expected to be 36% more than that of non-transfused patients, largely resulting from the development of SSIs.     

Fangchinoline as a kinase inhibitor targets FAK and suppresses FAK-mediated signaling pathway in A549

Background: Fangchinoline as a novel anti-tumor agent has been paid attention in several types of cancers cells except lung cancer. Here we have investigated the effect of fangchinoline on A549 cells and its underlying mechanism.

Purpose: The purpose of this work was to study the effect of fangchinoline on A549 cells.

Methods: Four lung cancer cell lines (A549, NCI-H292, NCI-H446, and NCI-H460) were exposed to varying concentrations (10–40?μmol/l) of fangchinoline to observe the effect of fangchinoline on the four lung cancer cell lines and to observe the changes of the lung cancer cell on proliferation, apoptosis, and invasion.

Results: Fangchinoline effectively suppressed proliferation and invasion of A549 cell line but not NCI-H292, NCI-H446, and NCI-H460 cell lines by inhibiting the phosphorylation of FAK (Tyr397) and its downstream pathways, due to the significant differences of Fak expression between A549 and the other three cell lines. And all FAK-paxillin/MMP2/MMP9 pathway, FAK-Akt pathway, and FAK-MEK-ERK1/2 pathway could be inhibited by fangchinoline.

Discussion: Fangchinoline effectively suppressed proliferation and invasion of A549 cell line by inhibiting the phosphorylation of FAK (Tyr397) and its downstream pathways.

Conclusion: Fangchinoline could inhibit the phosphorylation of FAK^p-Tyr397, at least partially. Fangchinoline as a kinase inhibitor targets FAK and suppresses FAK-mediated signaling pathway and inhibits the growth and the invasion in tumor cells which highly expressed FAK such as A549 cell line.     

Brucine,an effective natural compound derived from nux-vomica,induces G1 phase arrest and apoptosis in LoVo cells

Brucine is an alkaloid from nux vomica, has been shown various pharmacological actions. To study the possible anti-cancer mechanisms on LoVo cells, effects of Brucine on cell viability, cell cycle and apoptosis were investigated. The results showed that Brucine revealed strong growth inhibitory effect on LoVo cells, and caused LoVo cell shrinkage and membrane blobbing, induced cellular and DNA morphological changes. Cell cycle and apoptosis analysis documented that Brucine could change cell cycle and induce cell apoptosis. Brucine-mediated cell cycle arrest in G1 phase was associated with a marked increase of protein levels of CCND1 and decrease in CCNB1, cyclin E and CDC2. In addition, Brucine dose-dependently caused LoVo cells apoptosis evidenced by Annexin V/PI staining Brucine-induced apoptosis was mediated via up-regulation of Bax and down-regulation of Bcl-2. Furthermore, proteins Erk1/2, p38 and Akt phosphorylation were down regulated by Brucine in a dose-dependent manner. In summary, this paper indicates Brucine is effective against LoVo cells proliferation, and promotes LoVo cells death via apoptosis. These results reveal functional interplay among a series of pathway that are deregulated in cancer and suggest that their simultaneous targeting by Brucine could result in efficacious inhibition on cancer cells.     

Down‐regulation of KIF2A inhibits gastric cancer cell invasion via suppressing MT1‐MMP

Gastric cancer accounts for a sizeable proportion of global cancer mortality with high morbidity and poor prognosis. Kinesin superfamily proteins (KIFs) are microtubule‐dependent motor proteins that function as oncogenes in cancer cells, it has been discovered in recent years. Kinesin family member 2a (KIF2A), a member of the KIFs, has received attention for its role in carcinogenesis and its prognostic value in several human cancers such as breast cancer, colorectal cancer, and squamous cell carcinoma. However, the role of KIF2A in human gastric cancer remains unknown. In this study we aimed to explore the expression and biological functions of KIF2A in human gastric cancer cells, as well as to reveal its potential action mechanism. First, we found that KIF2A was markedly increased in gastric cancer cells (MKN‐28, MKN‐45, NCI‐N87 and SGC‐7901) compared to normal gastric mucosa epithelial cells (GES‐1). Then KIF2A was successfully silenced in MKN‐45 and SGC‐7901 cells to facilitate further research into its function. We discovered that KIF2A silencing can significantly inhibit the growth and invasion of MKN‐45 and SGC‐7901 cells in a time‐independent manner, accompanying a decreased expression of Membrane type 1‐matrix metalloproteinase (MT1‐MMP). When MT1‐MMP was reintroduced into MKN‐45 and SGC‐7901 cells in the KIF2A‐siRNA group, only invasion inhibition effects on MKN‐45 and SGC‐7901 cells induced by KIF2A silencing can be reversed. In conclusion, our study reveals that down‐regulation of KIF2A can inhibit gastric cancer cell invasion by suppressing MT1‐MMP.     

三氧化二砷对人大肠癌LoVo细胞血管内皮生长因子表达的影响

目的 探讨血管内皮生长因子(VEGF)在人大肠癌细胞株LoVo中的表达及三氧化二砷(As2O3)对其表达的影响.方法 应用实时定量PCR法和免疫细胞化学法检测As2O3干预前后LoVo结肠癌细胞中VEGF mRNA及VEGF蛋白表达.结果 LoVo大肠癌细胞表达VEGF,VEGF基因表达与蛋白表达呈正相关,且VEGF表达随着As2O3剂量的增加而下降.结论 VEGF在人结肠癌细胞LoVo中表达,As2O3可显著抑制VEGF的表达,呈剂量依赖性,表明As2O3具有抑制肿瘤血管生成的作用.     

5′-氮杂-2′-脱氧胞苷对 HT-29和 LoVo结直肠癌细胞株中 p16基因甲基化状态、mRNA表达及蛋白表达的影响

目的：探讨甲基化酶抑制剂5′-氮杂-2′-脱氧胞苷（5′-Aza-2′-deoxycytidine,5′-Aza-CdR）对结直肠癌细胞株HT-29和Lo-Vo中p16基因甲基化状态、mRNA及蛋白表达的影响。方法应用TaqMan探针为基础的实时定量PCR法、SYBR Green PCR法及蛋白印迹实验（ Western blot ）检测不同浓度5′-Aza-CdR处理前后HT-29和LoVo细胞中p16基因的甲基化状态、mRNA和蛋白表达。结果 TaqMan 探针为基础的实时定量PCR法检测HT-29和LoVo细胞中p16蛋白在药物作用后异常甲基化得到逆转;实时荧光定量PCR和Western Blot检测到0．5、1．0、1．5μM 5′-Aza-CdR处理后p16基因mRNA和蛋白均重新表达,具有统计学意义（P均＜0．05）。结论结直肠癌细胞株HT-29和LoVo中p16启动子甲基化可能是导致该基因表达下调甚至失活的主要原因。5′-Aza-CdR能够较成功的逆转结直肠癌细胞株HT-29和LoVo中p16基因的甲基化状态,并能恢复mRNA及蛋白重新表达。     

Lectin-mediated cytotoxicity and specificity of 5-fluorouracil conjugated with peanut agglutinin (5-Fu-PNA) in vitro

In order to take advantage of the biorecognition between lectin and carbohydrate for targeted drug delivery, the lectin of peanut (Arachis hypogaea) agglutinin (PNA) was coupled by fixing its amino groups to the carbodiimide-activated carboxylic groups of 5-fluorouracil (5-Fu) derivative (N₁-substituted 5-Fu acetate) to form 5-Fu-PNA conjugate. When the coupling reaction was carried out in the presence of _d-galactose (_d-gal, specific sugar for PNA), the affinity of PNA was maintained after its coupling to N₁-substituted 5-Fu acetate, which was confirmed by the result of the haemagglutination test. Otherwise, PNA would lose its affinity after the cross-linking reaction. The cytotoxicity, specificity and selectivity of 5-Fu-PNA were examined on the human colorectal cancer cell line LoVo and the human normal liver cell line Chang using MTT assay. Compared with free drug, the active conjugate, which maintained the affinity of lectin, had similar cytotoxic effect on LoVo cells with much lower cytotoxicity on Chang cells (p < 0.05). On the other hand, lower cytotoxic effects on LoVo cells were observed for the non-active conjugate even at higher drug concentrations. The cytotoxic effect of conjugate was specific because only the active conjugate could inhibit the growth of LoVo cells in a dose- and time-dependent manner as that of the free drug. The achieved results indicate the significance to maintain the affinity of lectin for lectin-mediated cytotoxicity. Still, the potential of 5-Fu-PNA conjugate as a targeting agent for colorectal cancer needs to be further investigated in vivo.     

Targeting IL-8 in colorectal cancer

Introduction: Colorectal cancer is the leading cause of death from gastrointestinal malignancy in the US. Chemokines and their receptors are being recognized as key regulators of cancers and increasingly as therapeutic targets for metastatic cancers, including colorectal cancer. Several studies have demonstrated that IL-8 and its receptor CXCR2 are two of the most significantly upregulated chemokines in colorectal cancer. IL-8 through binding to its receptors can act not only on inflammatory responses and infectious diseases, but also on cancer cells via their receptors to promote migration, invasion and proliferation, and in vivo angiogenesis. Therefore, IL-8 and CXCR2 may be important therapeutic targets against colorectal cancer.

Areas covered: This review provides an update on the roles of IL-8 and its receptors in colorectal cancer preclinical models and translational relevance: i) Increased expression of IL-8 and/or its receptors has been characterized in colon cancer cells; ii) IL-8 signaling pathway in colorectal cancer cells; iii) targeting IL-8 expression, or receptor-targeted strategies in colorectal cancer, eliminates the redundant function of IL-8 signaling and determines the effects of suppressing IL-8 signaling on tumor progression and development.

Expert opinion: IL-8 and its receptor CXCR2 may function as significant regulatory factors within the tumor microenvironment and be important therapeutic targets in colorectal cancers. Not only may they lead to antitumor properties, but also they may chemosensitize the tumor toward the current chemotherapy.     

全反式维甲酸提高人结肠癌LoVo细胞对奥沙利铂敏感性

目的探讨全反式维甲酸(all-trans retinoic acid,AT-RA)提高人结肠癌LoVo细胞对奥沙利铂的药物敏感性和机制。方法MTT法筛选ATRA和奥沙利铂实验浓度。流式细胞仪检测ATRA对细胞周期的影响。分别用ATRA、奥沙利铂、ATRA联合奥沙利铂作用LoVo细胞;MTT法检测药物抑制率,流式细胞仪检测细胞周期及凋亡率,原子光谱吸收仪检测细胞DNA含铂(Pt)量。结果奥沙利铂抑制LoVo细胞作用呈量效依赖;其GI50(GI,inhibit net cell growth by%)为6.5mg.L-1,主要阻滞肿瘤细胞在S期。ATRA抑制LoVo细胞作用呈时效和量效依赖。1.0μmol.L-1ATRA作用12h后G1期细胞增多;48h后伴S期、G2/M期细胞减少并明显抑制肿瘤细胞增殖;作用12h至48h后联合奥沙利铂,两药联合由相加作用转变为协同作用;联合用药后S期细胞明显增多,细胞DNA含Pt量明显增加,但不提高奥沙利铂凋亡率。结论小剂量ATRA通过改变LoVo细胞周期和提高细胞DNA含Pt量,明显增加肿瘤细胞对奥沙利铂的药物敏感性。     

Knockdown of GPR137,G Protein‐coupled receptor 137, Inhibits the Proliferation and Migration of Human Prostate Cancer Cells

GPR137 belongs to the G protein‐coupled receptor family involving the regulation of transmembrane signal transduction that launches pivotal cellular functions. However, its function in prostate cancer (PCa) has been rarely reported. It was found in this study that GPR137 was upregulated in PCa tissues as compared with that in paracancerous tissues. To see whether GPR137 could serve as a potential therapeutic target for PCa, GPR137 was knocked down to verify its biological function in PCa cells. Lentivirus‐introduced short hairpin RNA (shRNA) was designed to silence GPR137 gene. It was found that silencing of GPR137 gene suppressed the proliferation and colony formation of PCa cell lines PC‐3 and DU145. Further study indicated that growth inhibition by GPR137 knockdown was associated with cell cycle arrest at G0/G1 phase. Furthermore, silencing of GPR137 repressed the invasion and migration abilities of PC‐3 cells via downregulating slug and snail and upregulating E‐cadherin. Collectively, these findings imply that GPR137 plays an important role in the occurrence and progression of PCa and may prove to be a potential therapeutic target for the treatment of advanced PCa.