Systemically administered liposome-encapsulated Ad-PEDF potentiates the anti-cancer effects in mouse lung metastasis melanoma.

BACKGROUND: The use of adenoviral vector for gene therapy is still an important strategy for advanced cancers, however, the lack of the requisite coxsackie-adenovirus receptor in cancer cells and host immune response to adenovirus limit the application of adenoviral vector in vivo. METHOD: We designed the antiangiogenic gene therapy with recombinant PEDF adenovirus (Ad-PEDF) encapsulated in cationic liposome (Ad-PEDF/Liposome), and investigated the anti-tumor efficacy of Ad-PEDF/Liposome complex on inhibition of tumor metastasis. RESULTS: We found that systemic administration of Ad-PEDF/liposome was well tolerated and resulted in marked suppression of tumor growth, and was more potent than uncoated Ad-PEDF to induce apoptosis in B16-F10 melanoma cells and inhibit murine pulmonary metastases in vivo. After Ad-luciferase was encapsulated with liposome, its distribution decreased in liver and increased in lung. The anti-Ad IgG level of Ad-PEDF/Liposome was significantly lower than Ad-PEDF used alone. CONCLUSION: The present findings provide evidences of systematic administration of cationic liposome-encapsulated Ad-PEDF in pulmonary metastatic melanoma mice model, and show an encouraging therapeutic effect for further exploration and application of more complexes based on liposome-encapsulated adenovirus for more cancers.

[Liposomal curcumin inhibits tumor growth and angiogenesis in Lewis lung cancer].

OBJECTIVE: To prepare water soluble curcumin liposome and investigate its anti-tumour and antiangiogenic effects. METHODS: Liposomal curcumin was prepared by alcohol injection method. Proliferation inhibition to murin Lewis lung cancer cell line LL/2 of curcumin liposome was evaluated by MTT assay. Apoptosis and cell cycle arrest induced by liposomal curcumin were analysed by flow cytometry. Anti-tumour effects were investigated in a murine lung cancer model, and the anti-angiogenic effect was determined by aginate encapsulation assay. RESULTS: In vitro, liposomal curcumin inhibits the proliferation of LL/2 cells and induces apoptosis and cell cycle arrest. In vivo, the systemic administration of liposomal curcumin resulted in the inhibition of tumour. Aginate encapsulation assay revealed angiogenesis was decreased by curcumin liposome. CONCLUSION: The curcumin liposome treatment can significantly inhibit tumour growth in vivo.

AAV-mediated human PEDF inhibits tumor growth and metastasis in murine colorectal peritoneal carcinomatosis model.

BACKGROUND: Angiogenesis plays an important role in tumor growth and metastasis, therefore antiangiogenic therapy was widely investigated as a promising approach for cancer therapy. Recently, pigment epithelium-derived factor (PEDF) has been shown to be the most potent inhibitor of angiogenesis. Adeno-associated virus (AAV) vectors have been intensively studied due to their wide tropisms, nonpathogenicity, and long-term transgene expression in vivo. The objective of this work was to evaluate the ability of AAV-mediated human PEDF (hPEDF) as a potent tumor suppressor and a potential candidate for cancer gene therapy. METHODS: Recombinant AAV2 encoding hPEDF (rAAV2-hPEDF) was constructed and produced, and then was assigned for in vitro and in vivo experiments. Conditioned medium from cells infected with rAAV2-hPEDF was used for cell proliferation and tube formation tests of human umbilical vein endothelial cells (HUVECs). Subsequently, colorectal peritoneal carcinomatosis (CRPC) mouse model was established and treated with rAAV2-hPEDF. Therapeutic efficacy of rAAV2-hPEDF were investigated, including tumor growth and metastasis, survival time, microvessel density (MVD) and apoptosis index of tumor tissues, and hPEDF levels in serum and ascites. RESULTS: rAAV2-hPEDF was successfully constructed, and transmission electron microscope (TEM) showed that rAAV2-hPEDF particles were non-enveloped icosahedral shape with a diameter of approximately 20 nm. rAAV2-hPEDF-infected cells expressed hPEDF protein, and the conditioned medium from infected cells inhibited proliferation and tube-formation of HUVECs in vitro. Furthermore, in CRPC mouse model, rAAV2-hPEDF significantly suppressed tumor growth and metastasis, and prolonged survival time of treated mice. Immunofluorescence studies indicated that rAAV2-hPEDF could inhibit angiogenesis and induce apoptosis in tumor tissues. Besides, hPEDF levels in serum and ascites of rAAV2-hPEDF-treated mice were significant higher than those in rAAV2-null or normal saline (NS) groups. CONCLUSIONS: Thus, our results suggest that rAAV2-hPEDF may be a potential candidate as an antiangiogenic therapy agent.

Small molecule inhibitors targeting the cancers.

Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary targeted therapies for cancer. Due to their advantages in a wide range of targets, convenient medication, and the ability to penetrate into the central nervous system, many efforts have been devoted to developing more small molecule inhibitors. To date, 88 small molecule inhibitors have been approved by the United States Food and Drug Administration to treat cancers. Despite remarkable progress, small molecule inhibitors in cancer treatment still face many obstacles, such as low response rate, short duration of response, toxicity, biomarkers, and resistance. To better promote the development of small molecule inhibitors targeting cancers, we comprehensively reviewed small molecule inhibitors involved in all the approved agents and pivotal drug candidates in clinical trials arranged by the signaling pathways and the classification of small molecule inhibitors. We discussed lessons learned from the development of these agents, the proper strategies to overcome resistance arising from different mechanisms, and combination therapies concerned with small molecule inhibitors. Through our review, we hoped to provide insights and perspectives for the research and development of small molecule inhibitors in cancer treatment.

Polyclonal rabbit anti-murine plasmacytoma cell globulins induce myeloma cells apoptosis and inhibit tumour growth in mice.

Multiple myelomas (MMs) are etiologically heterogeneous and there are limited treatment options; indeed, current monoclonal antibody therapies have had limited success, so more effective antibodies are urgently needed. Polyclonal antibodies are a possible alternative because they target multiple antigens simultaneously. In this study, we produced polyclonal rabbit anti-murine plasmacytoma cell immunoglobulin (PAb) by immunizing rabbits with the murine plasmacytoma cell line MPC-11. The isolated PAb bound to plasma surface antigens in several MM cell lines, inhibited their proliferation as revealed by MTT assay, and induce apoptosis as indicated by flow cytometry, microscopic observation of apoptotic changes in morphology, and DNA fragmentation on agarose gels. The cytotoxicity of PAb on MPC-11 cell lines was both dose-dependent and time-dependent; PAb exerted a 50% inhibitory effect on MPC-11 cell viability at a concentration of 200 µg/ml in 48 h. Flow cytometry demonstrated that PAb treatment significantly increased the number of apoptotic cells (48.1%) compared with control IgG (8.3%). Apoptosis triggered by PAb was confirmed by activation of caspase-3, -8, and -9. Serial intravenous or intraperitoneal injections of PAb inhibited tumour growth and prolonged survival in mice bearing murine plasmacytoma, while TUNEL assay demonstrated that PAb induced statistically significant apoptosis (P < 0.05) compared to control treatments. We conclude that PAb is an effective agent for in vitro and in vivo induction of apoptosis in multiple myeloma and that exploratory clinical trials may be warranted.

[Antitumor effect by combination of shRNA interfering plasmid targeting PKM2 with recombinant endostatin].

OBJECTIVE: To investigate the enhancement effect of the combination of shRNA interfering plasmid targeting PKM2 with recombinant Endostatin in the treatment of lung cancer. METHODS: Twenty five BABL/nu/nu mice bearing A549 lung cancer were divided into 5 groups (NS control, psh-Control, psh-PKM2 treated group, Endostar treated group, psh-PKM2+Endostar treated group) and treated with shRNA interfering plasmid targeting PKM2 and recombinant Endostatin respectively or in combination. The expression of PKM2 in A549 detected with immunofluorescent assay. The interference effect of psh-PKM2 was determined by Western blot. The tumor volume, microvessel density (MVD), apoptosis index (AI) and side effects were observed. RESULTS: The combination treatment of RNA interfering plasmid targeting PKM2 with recombinant Endostatin inhibited tumor growth obviously (P < 0.05); The combination group revealed a decreased MVD and an increased AI (P < 0.05). CONCLUSION: The combination of shRNA interfering plasmid targeting PKM2 with recombinant Endostatin might enhance anti-tumor effect by increasing the apoptosis of the cancer cell.

Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model.

Murine studies have shown that immunological targeting of fibroblast activation protein (FAP) can elicit protective immunity in the absence of significant pathology. Fibroblast activation protein is a product overexpressed by tumor-associated fibroblasts (TAF) and is the predominant component of the stoma in most types of cancer. Tumor-associated fibroblasts differ from normal adult tissue fibroblasts, and instead resemble transient fetal and wound healing-associated fibroblasts. Tumor-associated fibroblasts are critical regulators of tumorigenesis, but differ from tumor cells by being more genetically stable. Therefore, in comparison to tumor cells, TAF may represent more viable therapeutic targets for cancer immunotherapy. To specifically target TAF, we constructed a DNA vaccine directed against FAP. This vaccine significantly suppressed primary tumor and pulmonary metastases primarily through CD8(+) T-cell-mediated killing in tumor-bearing mice. Most importantly, tumor-bearing mice vaccinated against FAP exhibited a 1.5-fold increase in lifespan and no significant pathology. These results suggest that FAP, a product preferentially expressed by TAF, could function as an effective tumor rejection antigen.

Silencing of pkm2 increases the efficacy of docetaxel in human lung cancer xenografts in mice.

Tumor aerobic glycolysis, or the Warburg effect, plays important roles in tumor survival, growth, and metastasis. Pyruvate kinase isoenzyme M2 (PKM2) is a key enzyme that regulates aerobic glycolysis in tumor cells. Recent research has shown that PKM2 can be used as a tumor marker for diagnosis and, in particular, as a potential target for cancer therapy. We investigated the effects of combining shRNA targeting PKM2 and docetaxel on human A549 lung carcinoma cells both in vivo and in vitro. We observed that the shRNA can significantly downregulate the expression level of PKM2. The decrease of PKM2 resulted in a decrease in ATP synthesis, which caused intracellular accumulation of docetaxel. Furthermore, the combination of pshRNA-pkm2 and docetaxel inhibited tumor growth and promoted more cancer cell apoptosis both in vivo and in vitro. Our findings suggest that targeting tumor glycolysis can increase the efficacy of chemotherapy. In particular, the targeting of PKM2 could, to some extent, be a new way of reversing chemotherapy resistance to cancer therapy.

[Antitumor effect by combination of recombinant endostatin adenovirus with carboplatin].

OBJECTIVE: To investigate the antitumor effect of recombinant Endostatin adenovirus (Ad-E) with carboplatin in mice with Lewis lung cancer. METHODS: C57BL/6 mice bearing Lewis lung cancer received Ad-E and carboplatin respectively or in combination. The tumor volume, tumor net weight, survival time and side effects were observed. Histological analysis was conducted to assess microvessel density (MVD) within tumor tissue and apoptotic cells were identified using the TUNEL assay. RESULTS: Compared with the control groups, the combination treatment significantly suppressed the tumor growth and prolonged survival time of the mice without obvious side-effects. The histological analysis revealed the combination treatment led to a decreased MVD and increased percent apoptosis in LL/2 tumors. CONCLUSION: Our studies indicate that a combination of Ad-E with carboplatin can present better antitumor effects without obvious side-effect.

The Promotion of Erythropoiesis via the Regulation of Reactive Oxygen Species by Lactic Acid.

The simultaneous increases in blood lactic acid and erythrocytes after intense exercise could suggest a link between lactate and the erythropoiesis. However, the effects of lactic acid on erythropoiesis remain to be elucidated. Here, we utilized a mouse model to determine the role of lactic acid in this process in parallel with studies using leukaemic K562 cells. Treatment of K562 cells in vitro with lactic acid increased the mRNA and protein expression of haemoglobin genes and the frequency of GPA+ cells. Also, increases in haematocrit and CD71-/Ter119+ erythroid cells were observed in lactic acid-treated mice, which showed a physiological increase in blood lactate. Mouse bone marrow CD34+/CD117- cells showed an increase in erythroid burst-forming units after stimulation with lactic acid in vitro. Furthermore, lactic acid increased the intracellular reactive oxygen species (ROS) content in bone marrow and in K562 cells. Erythroid differentiation induced in Haematopoietic Stem Cells (HSCs) and K562 cells by lactic acid was abolished by reducing ROS levels with SOD or 2-mercaptoethanol, which suggests that ROS is a critical regulator of this process. These findings provide a better understanding of the role of lactic acid in cellular metabolism and physiological functions.

Targeting pyruvate kinase M2 contributes to radiosensitivity of non-small cell lung cancer cells in vitro and in vivo.

Aerobic glycolysis, a metabolic hallmark of cancer, is associated with radioresistance in non-small cell lung cancer (NSCLC). Pyruvate kinase M2 isoform (PKM2), a key regulator of glycolysis, is expressed exclusively in cancers. However, the impact of PKM2 silencing on the radiosensitivity of NSCLC has not been explored. Here, we show a plasmid of shRNA-PKM2 for expressing a short hairpin RNA targeting PKM2 (pshRNA-PKM2) and demonstrate that treatment with pshRNA-PKM2 effectively inhibits PKM2 expression in NSCLC cell lines and xenografts. Silencing of PKM2 expression enhanced ionizing radiation (IR)-induced apoptosis and autophagy in vitro and in vivo, accompanied by inhibiting AKT and PDK1 phosphorylation, but enhanced ERK and GSK3ß phosphorylation. These results demonstrated that knockdown of PKM2 expression enhances the radiosensitivity of NSCLC cell lines and xenografts as well as may aid in the design of new therapies for the treatment of NSCLC.

Chemo-immunotherapy with oxaliplatin and interleukin-7 inhibits colon cancer metastasis in mice.

Combination of immunotherapy and chemotherapy has shown promise for cancer. Interleukin-7 (IL-7) can potentially enhance immune responses against tumor, while oxaliplatin (OXP), a platinum-based drug, can promote a favorable immune microenvironment and stimulate anticancer immune responses. We evaluated the anti-tumor activity of IL-7 combining OXP against a murine colon carcinoma in vitro and in vivo and studied the tumor immune microenvironment to investigate whether the combined treatment affects on the local immune cell populations. Utilizing lung and abdomen metastasis models by inoculation of CT26 mice colon cancer cells, we evaluated the anti-tumor efficacy of combining IL-7 and OXP in mice models. Tumor immune microenvironment was evaluated by flow cytometric analysis and immunohistochemical staining. Our study showed that the in vivo administration of IL-7 combined with OXP markedly inhibited the growth of tumors in lung and abdomen metastasis models of colon cancer. IL-7 alone had no effect on tumor growth in mice and IL-7 did not alter cell sensitivity to OXP in culture. The antitumor effect of combining IL-7 and OXP correlated with a marked increase in the number of tumor-infiltrating activated CD8+ T cells and a marked decrease in the number of regulatory T (Treg) cells in spleen. Our data suggest that OXP plus IL-7 treatment inhibits tumor cell growth by immunoregulation rather than direct cytotoxicity. Our findings justify further evaluation of combining IL-7 and chemotherapy as a novel experimental cancer therapy.

Gene therapy with beta-defensin 2 induces antitumor immunity and enhances local antitumor effects.

Beta-defensins, small antimicrobial peptides, are involved in host immune responses to tumors. In this study, we used beta-defensin 2 (BD2) to explore the possible role of beta-defensins in cancer gene therapy. A recombinant plasmid expressing a secretable form of BD2 was constructed. The biological activities of BD2 in immature dendritic cells (iDCs) were tested in vitro and in vivo. The antitumor effects were investigated in three established tumor models. The secreted BD2 was detected and exhibited chemotactic activity in iDCs both in vitro and in vivo. Recruitment and activation of iDCs in tumor niches resulted in significant tumor growth inhibition. Adoptive transfer of splenocytes and depletion of immune cell subsets revealed that CD8(+) T lymphocyte responses mediated the increased tumor inhibition. Furthermore, we also found that chemotactic and maturation-inducing activities in iDCs in tumor milieu contributed to enhanced local antitumor effects. Our study indicates that gene therapy with BD2 can mediate specific antitumor immunity and augment local antitumor effects. Our study also suggested that beta-defensins may merit further exploration for cancer immunotherapy as promising immunogenes.

Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model.

Human neutrophil peptides (HNPs) 1-3 possess a high degree of similarity and are deregulated in many types of human tumors. Previous studies have demonstrated that tumor cell lines and microdissected fresh tumor cells express HNP1-3. In vitro, HNP1-3 have been reported to be cytotoxic to various types of tumor cells. Previously, we observed that the intracellular expression of HNP1 increased plasma membrane permeability in A549 cells and inhibited in vivo tumor angiogenesis. Based on these findings, we inferred that the intratumoral expression of HNP1 may benefit chemotherapy in solid tumors. In the present study, we established a mouse 4T1 breast cancer model imitating locally advanced breast cancer (LABC) and we injected the mice intratumorally with plasmid HNP1 (pHNP1). Doxorubicin (Dox) was administered twice i.v. at 5 mg/kg body weight on day 1 and 8. The possible mechanisms were investigated by evaluating cell proliferation and apoptosis, intracellular Dox accumulation, mitochondrial transmembrane potential (ΔΨm) and ultrastructural alteration of intratumoral microvessels. Compared with the single agent treatment, the combination of Dox and pHNP1 resulted in a significant delay in in vivo tumor growth and a decrease in lung metastasis. This chemosensitization effect was also observed in an A549 lung cancer model treated with cisplatin (DDP) and pHNP1. MTT assay and Annexin V staining demonstrated that 4T1 cells pre-transfected with pHNP1 were significantly more sensitive to Dox, causing increased proliferation inhibition and apoptosis. Further investigations showed that the intracellular expression of HNP1 enhanced Dox accumulation and significantly impaired mitochondrial ΔΨm. Moreover, in tumor tissues, HNP1 mediated intratumoral microvessel normalization and caused significant in situ tumor cell apoptosis. Our study suggests that intratumoral expression of HNP1 can significantly improve the therapeutic efficacy of Dox in breast cancer, abrogate the influence of multidrug resistance and enhance medication safety. Our findings may be important for the clinical therapeutic strategies of cancer chemotherapy.

Synergic antitumor effect of SKLB1002 and local hyperthermia in 4T1 and CT26.

A de novo VEGFR2-inhibited compound SKLB1002 which is independently developed in our laboratory has been described for antiangiogenesis and displays a potent antitumor activity in vivo and in vitro. In the present investigation, we aim to prove that combination therapy of SKLB1002 with hyperthermia plays a synergy as an antitumor agent in solid tumor. In this study, we analyzed their synergetic inhibitory action on human umbilical vein endothelial cells (HUVEC), murine mammary cancer 4T1, murine colon carcinoma CT26 in vitro. Multiply-table tournament was performed to detect cell proliferation in vitro. 4T1 implantation and CT26 implantation in BALB/c mice were used to examine the activity of combination therapy of SKLB1002 with hyperthermia in vivo. Vascular density was determined by CD31 immunohistochemistry. TUNEL was used to measure apoptosis in tumor tissue. Metastasis assay was investigated via measurement of pulmonary metastasis nodules under the microscope. Potential toxicity of combination therapy was observed by histologic analysis of main organs stained with H&E. In vitro, the combination therapy significantly inhibited cell proliferation of HUVEC, 4T1 and CT26. In vivo, 4T1 and CT26 model experiments showed that combination therapy remarkably inhibited tumor growth and prolonged life span. When compared with controls, combination therapy reached 61 % inhibition index of tumor growth against CT26 and 51 % against 4T1. Moreover, it reduced angiogenesis and increased tumor apoptosis and necrosis. It was further found that combination therapy could efficiently prevent tumor from metastasizing to lung. Importantly, it had no toxicity to main organs including heart, liver, spleen, lung and kidney. Combination treatment has been proved to be a novel and strong strategy in clinical antitumor therapy. Our findings suggest that the combination therapy of SKLB1002 with hyperthermia has a synergistic antiangiogenesis, anticancer and promotion of apoptosis efficacy compared with controls. These findings could pave a new way in clinical tumor therapy.

Accumulation of FLT3(+) CD11c (+) dendritic cells in psoriatic lesions and the anti-psoriatic effect of a selective FLT3 inhibitor.

Psoriasis is a common chronic T-cell-mediated autoimmune skin disease, and traditional immunotherapies for psoriasis have focused on the direct inhibition of T cells, which often causes toxicity and lacks long-term effectiveness. Safe and effective therapeutic strategies are strongly needed for psoriasis. In this study, we show for the first time a significant accumulation of FLT3(+) CD11c(+) dendritic cells (DCs) in human psoriatic lesions and in the skin of experimental preclinical K14-VEGF transgenic homozygous mice, our animal model, although not an exact match for human psoriasis, displays many characteristics of inflammatory skin inflammation. SKLB4771, a potent and selective FLT3 inhibitor that we designed and synthesised, was used to treat cutaneous inflammation and psoriasis-like symptoms of disease in mice and almost completely cured the psoriasis-like disease without obvious toxicity. Mechanistic studies indicated that SKLB4771 treatment significantly decreased the number and activation of pDCs and mDCs in vitro and in vivo, and subsequent T-cell cascade reactions mediated by Th1/Th17 pathways. These findings show that targeted inhibition of FLT3, and hence direct interference with DCs, may be a novel therapeutic approach for the treatment of psoriasis.

Ad-endostatin treatment combined with low-dose irradiation in a murine lung cancer model.

Radiation therapy is a conventional strategy for treating advanced lung cancer yet is accompanied by serious side-effects. Its combination with other strategies, such as antiangiogenesis and gene therapy, has shown excellent prospects. As one of the potent endogenous vascular inhibitors, endostatin has been widely used in the antiangiogenic gene therapy of tumors. In the present study, LL/2 cells were infected with a recombinant adenovirus encoding endostatin (Ad-endostatin) to express endostatin. The results showed that LL/2 cells infected with the Ad-endostatin efficiently and longlastingly expressed endostatin. In order to further explore the role of Ad-endostatin combined with irradiation in the treatment of cancer, a murine lung cancer model was established and treated with Ad-endostatin combined with low-dose irradiation. The results showed that the combination treatment markedly inhibited tumor growth and metastasis, and prolonged the survival time of the tumor-bearing mice. Furthermore, this significant antitumor activity was associated with lower levels of microvessel density and anoxia factors in the Ad-Endo combined with irradiation group, and with an increased apoptotic index of tumor cells. In addition, no serious side-effects were noted in the combination group. Based on our findings, Ad-endostatin combined with low-dose irradiation may be a rational alternative treatment for lung cancer and other solid tumors.

Enhanced antitumor effect of curcumin liposomes with local hyperthermia in the LL/2 model.

Curcumin previously was proven to inhibit angiogenesis and display potent antitumor activity in vivo and in vitro. In the present study, we investigated whether a combination curcumin with hyperthermia would have a synergistic antitumor effect in the LL/2 model. The results indicated that combination therapy significantly inhibited cell proliferation of MS-1 and LL/2 in vitro. LL/2 experiment model also demonstrated that the combination therapy inhibited tumor growth and prolonged the life span in vivo. Furthermore, combination therapy reduced angiogenesis and increased tumor apoptosis. Our findings suggest that the combination therapy exerted synergistic antitumor effects, providing a new perspective fpr clinical tumor therapy.

K­ras gene mutation as a predictor of cancer cell responsiveness to metformin.

An increasing number of studies support the use of metformin, a common antidiabetic drug, as a novel anticancer therapeutic. However, its mechanism of action has yet to be identified. In the current study, metformin was observed to effectively inhibit the growth of the K-ras mutant but not wild-type tumors in vivo. The antitumor effects of metformin were mediated by the induction of apoptosis and inhibition of proliferation in vivo. In addition, metformin induced apoptosis in the K-ras mutant tumors, A549 and PANC-1, but not in the K-ras wild-type tumor, A431, in vitro. Similarly, at lower concentrations, metformin inhibited cell proliferation in the K-ras mutant, but not in the K-ras wild-type tumor cells in vitro. These observations indicate that tumors with K-ras mutations are sensitive to metformin therapy. In addition, metformin significantly arrested K-ras mutant and wild-type tumor cells in G1 phase in vitro and metformin downregulated two important downstream effectors of the Ras signaling pathway in K-ras mutant tumors. Metformin was concluded to function as a potential K-ras-targeting agent that has potential for cancer therapy.

Quercetin liposome sensitizes colon carcinoma to thermotherapy and thermochemotherapy in mice models.

Thermotherapy and thermochemotherapy have been used in clinics to treat patients with malignant diseases, including colon cancer, and their efficacy has been well proved. Heat shock proteins (HSPs), especially Hsp70, play important roles in neutralizing their efficacy. It has been reported that quercetin can suppress cancer by inhibiting the intratumoral expression of Hsp70. This study was designed to investigate whether quercetin could enhance sensitivity to thermotherapy and thermochemotherapy. Soluble quercetin liposome was used in this study. The effects of quercetin were investigated in vitro and in mouse colon cancer models of subcutaneous tumor and peritoneal carcinomatosis. The results showed that quercetin liposome inhibited the upregulation of Hsp70 and enhanced apoptosis induced by hyperthermia and thermochemotherapy. Systemic administration of quercetin liposome can sensitize CT26 cells to thermotherapy and chemothermotherapy. This study suggests that quercetin liposome might be potentially applied for clinical cancer therapy.