Xiao-Bo Du

Liposomal Quercetin Efficiently Suppresses Growth of Solid Tumors in Murine Models

Purpose: Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin have been hampered by its extreme water insolubility. To overcome this limitation, this study is aimed to develop liposomal quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro. Experimental Design: Quercetin was encapsulated in polyethylene glycol 4000 liposomes. Biodistribution of liposomal quercetin i.v. at 50 mg/kg in tumor-bearing mice was detected by high-performance liquid chromatography. Induction of apoptosis by liposomal quercetin in vitro was tested. The antitumor activity of liposomal quercetin was evaluated in the immunocompetent C57BL/6N mice bearing LL/2 Lewis lung cancer and in BALB/c mice bearing CT26 colon adenocarcinoma and H22 hepatoma. Tumor volume and survival time were observed. The mechanisms underlying the antitumor effect of quercetin in vivo was investigated by detecting the microvessel density, apoptosis, and heat shock protein 70 expression in tumor tissues. Results: Liposomal quercetin could be dissolved in i.v. injection and effectively accumulate in tumor tissues. The half-time of liposomal quercetin was 2 hours in plasma. The liposomal quercetin induced apoptosis in vitro and significantly inhibited tumor growth in vivo in a dose-dependent manner. The optimal dose of liposomal quercetin resulted in a 40-day survival rate of 40%. Quantitative real-time PCR showed that liposomal quercetin down-regulated the expression of heat shock protein 70 in tumor tissues. Immunohistochemistry analysis showed that liposomal quercetin inhibited tumor angiogenesis as assessed by CD31 and induced tumor cell apoptosis. Conclusions: Our data indicated that pegylated liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be a potential application in the treatment of tumor.

Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes.

It has been reported that antidiabetic drugs affect the risk of cancer and the prognosis of patients with diabetes, but few studies have demonstrated the influence of different antidiabetic agents on outcomes after anticancer therapy among patients with cancer. The objective of this study was to evaluate the influence of the antidiabetic drugs metformin and insulin on the prognosis of patients with advanced nonsmall cell lung cancer (NSCLC) plus type 2 diabetes who received first‐line chemotherapy.

Immunohistochemical detection of the Raf kinase inhibitor protein in nonneoplastic gastric tissue and gastric cancer tissue.

Expression of the Raf kinase inhibitor protein (RKIP), a metastasis suppressor, is high in normal tissues, low in primary cancers, and lowest or absent in metastatic cancers. Here, we studied the expression of RKIP in nonneoplastic gastric tissue and gastric cancer tissue by immunohistochemistry (IHC) and evaluated its role in the genesis and metastasis of gastric cancer. RKIP immunoreactivity was evaluated in 40 samples of nonneoplastic gastric tissues and 75 samples of gastric cancer tissues. Among the 40 samples of nonneoplastic gastric tissue, 35 (87.5%) were positive for RKIP expression and 5 (12.5%) were negative; in the 75 samples of primary gastric cancer tissue, 39 (52%) were positive for RKIP expression and 36 (48%) were negative. Among 26 samples of metastatic lymph node tissues, 5 (19.2%) were positive for RKIP expression and 21 (80.8%) were negative. RKIP expression level was highest in nonneoplastic gastric tissue, low in primary gastric cancer tissue, and lowest or undetectable in metastatic gastric cancer tissue. Our data suggest that RKIP may play a role in the genesis and metastasis of gastric cancer.

A promising cancer gene therapy agent based on the matrix protein of vesicular stomatitis virus

The matrix (M) protein of vesicular stomatitis virus (VSV) plays a key role in inducing cell apoptosis during infection. To investigate whether M protein‐mediated apoptosis could be used in cancer therapy, its cDNA was amplified and cloned into eukaryotic expression vector pcDNA3.1(+). The recombinant plasmid or the control empty plasmid pcDNA3.1(+) was mixed with cationic liposome and introduced into various tumor cell lines in vitro, including lung cancer cell LLC, A549, colon cancer cell CT26 and fibrosarcoma cell MethA. Our data showed that the M protein induced remarkable apoptosis of cancer cells in vitro compared with controls. Fifty micrograms of plasmid in a complex with 250 μg cationic liposome was injected intratumorally into mice bearing LLC or MethA tumor model every 3 days for 6 times. It was found that the tumors treated with M protein plasmid grew much more slowly, and the survival of the mice was significantly prolonged compared with the mice treated with the control plasmid. In MethA fibrosarcoma, the tumors treated with M protein plasmid were even completely regressed, and the mice acquired longtime protection against the same tumor cell in rechallenge experiments. Both apoptotic cells and CD8+ T cells were widely distributed in M protein plasmid‐treated tumor tissue. Activated cytotoxic T lymphocytes (CTLs) were further detected by means of 51Cr release assay in the spleen of the treated mice. These results showed that M protein of VSV can act as both apoptosis inducer and immune response initiator, which may account for its extraordinary antitumor effect and warrant its further development in cancer gene therapy.— Zhao, J., Wen, Y., Li, Q., Wang, Y., Wu, H., Xu, J., Chen, X., Wu, Y., Fan, L., Yang, H., Liu, T., Ding, Z., Du, X., Diao, P., Li, J., Wu, H., Kan, B., Lei, S., Deng, H., Mao, Y., Zhao, X., Wei, Y. A promising cancer gene therapy agent based on the matrix protein of vesicular stomatitis virus. FASEB J. 22, 4272–4280 (2008)

Vesicular stomatitis virus matrix protein gene enhances the antitumor effects of radiation via induction of apoptosis

Vesicular stomatitis virus (VSV) matrix (M) protein can directly induce apoptosis by inhibiting host gene expression when it is expressed in the absence of other viral components. Previously, we found that the M protein gene complexed to DOTAP-cholesterol liposome (Lip-MP) can suppress malignant tumor growth in vitro and in vivo; however, little is known regarding the biological effect of Lip-MP combined with radiation. The present study was designed to determine whether Lip-MP could enhance the antitumor activity of radiation. LLC cells treated with a combination of Lip-MP and radiation displayed apparently increased apoptosis compared with those treated with Lip-MP or radiation alone. Mice bearing LLC or Meth A tumors were treated with intratumoral or intravenous injections of Lip-MP and radiation. The combined treatment significantly reduced mean tumor volumes compared with either treatment alone in both tumor models and prolonged the survival time in Meth A tumor models and the intravenous injection group of LLC tumor models. Moreover, the antitumor effects of Lip-MP combined with radiation were greater than their additive effects when compared with the expected effects of the combined treatment in vivo. This study suggests that Lip-MP enhanced the antitumor activity of radiation by increasing the induction of apoptosis.

Survey on breast cancer patients in China toward breast‐conserving surgery

Objective: We sought to investigate attitudes toward breast‐conserving therapy (BCS) in early‐stage breast cancer (EBC) patients from P. R. China and assess the factors influencing their decision.

Induction of apoptosis by phenylisocyanate derivative of quercetin: involvement of heat shock protein.

Quercetin, a widely distributed bioflavonoid, inhibits the growth of various tumor cells. The present study was designed to investigate whether a novel quercetin derivative [phenylisocyanate of quercetin (PHICNQ)] exerts antitumor activity against K562 and CT26 tumor cell lines by inducing apoptosis, and to examine the possible mechanism in the phenomenon. The cell proliferation assay of K562 and CT26 tumor cells was determined by the trypan blue dye exclusion test. Apoptosis of PHICNQ-treated cells was determined by morphological analysis, agarose gel DNA electrophoresis and quantitated by flow cytometry after staining with propidium iodide. Cell cycle was evaluated by flow cytometry. The expression of heat shock protein 70 was checked by Western blot analysis. Our results showed that PHICNQ inhibited the proliferation of K562 and CT26 cells in a dose-dependent and time-dependent manner. PHICNQ was 308- and 73-fold more active on CT26 and K562 cells than quercetin, respectively. In addition to this cytostatic effect, treatment of K562 and CT26 tumor cells with PHICNQ induced apoptosis. PHICNQ treatment downregulated the expression of heat shock protein 70 more dramatically than quercetin treatment. These results suggest that PHICNQ is a more powerful antiproliferative derivative than quercetin, with cytostatic and apoptotic effects on K562 and CT26 tumor cells. PHICNQ may trigger apoptosis in tumor cells through inhibition of heat shock protein 70 synthesis and expression.

Attitudes and behavior of radiation oncologists toward sexual issues of cervical cancer patients who receive radiation therapy: a survey in China.

Objective Cervical cancer is known to impair women’s sexual function. This study aimed at investigating the attitudes and behavior of radiation oncologists regarding sexual functioning of female cervical cancer patients who receive radiation therapy. Methods A total of 186 radiation oncologists were included. A self-reported questionnaire was used to investigate the attitudes and behavior of radiation oncologists. The oncologists were queried on their history of consultation on sexual issues, attitudes, and behavior toward sexual issues and considerations of sexual life for cervical cancer patients who receive radiotherapy. Results Among 120 radiation oncologists who completed the questionnaires, 101 (84.2%) had been consulted on sexual issues, of whom only 29 (24.2%) were consulted by more than 10% of cervical cancer patients who received radiation therapy or their families. Compared with those without a history of consultation, radiation oncologists with a history of consultation were more likely to agree that “radiation oncologists should deal with a patient’s sexual issues” (88.1% vs 68.4%) and disagree that “sex is private and should not be interfered with” (66.2% vs 44.5%). Five radiation oncologists (4.2%) had received special training to deal with the sexual issues of cervical cancer patients who receive radiotherapy, and 112 oncologists (93.3%) did not have any information on sexual functioning to give the their patients. Conclusions History of consultation on sexual issues affects radiation oncologists’ attitudes and behavior toward sexual issues of cervical cancer patients. Radiation oncologists should have a more positive attitude toward sexual issues and should receive more specific relevant training.

Overexpression of Y-box binding protein-1 in cervical cancer and its association with the pathological response rate to chemoradiotherapy

The aim of this study was to evaluate the expression of Y-box binding protein-1 (YB-1) in nonneoplastic cervical tissue and cervical cancer tissue and to evaluate its relationship with chemoradiosensitivity in the cases of cervical cancer. We performed immunohistochemical studies to examine YB-1 expression among 59 patients with cervical cancer, 30 with cervical intraepithelial neoplasia (CIN), and 30 with cervicitis. The mean YB-1 histological score(HSCORE)values for cervicitis, cervical CIN, and cervical cancer tissues were 22.3, 39, and 84.4, respectively. The mean YB-1 HSCORE value was 80.0 for cervical cancer patients who showed complete pathological response to chemoradiotherapy and 144.3 for cervical cancer patients who showed partial pathological response. Our data showed that the YB-1 expression was the highest in cervical cancer tissue, followed by cervical CIN tissue, and then cervicitis tissues. High YB-1 expression resulted in a lower pathological response rate in patients of cervical cancer than low YB-1 expression did. Our results implied that YB-1 may play a role in the genesis of cervical cancer and that high YB-1 expression decreases the chemoradiosensitivity of cervical cancers.

Significance of Serum Total Oxidant/Antioxidant Status in Patients with Colorectal Cancer.

Oxidative stress is involved in a variety of diseases. Prospective studies investigating the relationship between oxidative stress biomarkers and the status and development of colorectal cancer (CRC) are scarce; previous studies have failed to establish a relationship between the serum total oxidant/antioxidant status and CRC. Therefore, we compared the total serum oxidant/antioxidant levels of CRC patients and healthy subjects, and analyzed their clinical significance in the CRC. Fasting blood samples from 132 CRC patients and 64 healthy subjects were collected. Oxidative stress parameters, including total oxidant status (TOS) and total antioxidant status (TAS), were measured, and the oxidative stress index (OSI) was calculated. The TOS and OSI levels increased significantly (P<0.001) and the TAS level significantly decreased (P<0.001) in the CRC group compared to those in the healthy control group. Oxidative stress parameters differed significantly depending on the patient’s smoking and drinking status (P<0.05). The preoperative and postoperative levels of TOS, TAS, and OSI did not differ significantly between primary sites (colon/rectum) and clinical stages (P>0.05).However, the levels of TOS, TAS, and OSI were significantly different between patients with no metastasis and those with metastases to two organs (P<0.05) Finally, the parameters are affected by smoking and drinking, and subsequent research should be conducted excluding the relevant influencing factors.