Life Span Of Tumor-bearing Mice Research Articles

Size-controllable food-grade nanoparticles based on sea cucumber polypeptide with good anti-oxidative capacity to prolong lifespan in tumor-bearing mice

Liver cancer, a malignancy with a rising global incidence, poses a significant challenge in achieving effective treatment outcomes. As food-derived nutrient, sea cucumber peptide (SCP) has shown promising anticancer effects. Therefore, we explored the nanodelivery systems to encapsulate SCP to enhance its stability in the gastrointestinal tract and improve absorption within the tumor microenvironment. This study aimed to develop size-controllable multifunctional nanoparticles using SCP, procyanidins (PCs), and vanillin through molecular assembly via a one-pot Mannich condensation approach. These food-grade nanoparticles demonstrated water solubility and exhibited a spherical structure with sizes ranging from 441 to 1360 nm, depending on the concentration of the reactants. In vitro cell experiments demonstrated that SCP nanoparticles modified with PCs effectively reduced the generation of reactive oxygen species from H2O2 and acrylamide while maintaining normal levels of mitochondrial membrane potential. Furthermore, in vivo nutrition intervention studies conducted on tumor-bearing mice revealed that mice treated with SCP nanoparticles exhibited a survival rate of 40 %, which was significantly higher than the 0 % and 20 % survival rates observed in the control and SCP-treated groups, respectively. These findings suggest that SCP nanoparticles, possessing antioxidative properties and controllable sizes, hold potential for precision nutrition in the field of cancer treatment.

Two-Dimensional FePS3 Nanosheets as an Integrative Sonosensitizer/Nanocatalyst for Efficient Nanodynamic Tumor Therapy.

As the emerging modalities for tumor therapy, sonodynamic therapy (SDT) and chemodynamic therapy (CDT) can generate reactive oxygen species (ROS), typically inducing tumor cell apoptosis. However, the construction of more efficient sonosensitizers integrated with excellent Fenton/Fenton-like catalytic activity to improve the synergistic therapeutic effect of SDT and CDT is still highly challenging. In this study, 2D semiconductor FePS3 nanosheets (NSs), as one of the metal phosphorus trichalcogenides for both sonosensitizer and Fenton catalyst, are successfully synthesized via an ultrasonic-assisted liquid phase exfoliation method from bulk FePS3 and further modified with lipoic acid-polyethylene glycol (LA-PEG) to obtain FePS3 -PEG NSs with desirable biocompatibility. The in vitro and in vivo results demonstrate that the engineered FePS3 -PEG NSs induce the combinatorial SDT/CDT effect attributing to the enhanced ROS generation and significant glutathione depletion, which can conduct highly efficient and safe tumor inhibition and prolong the life span of tumor-bearing mice. This work provides the paradigm of semiconductor FePS3 NSs as the integrative sonosensitizer/Fenton nanocatalyst for dual nanodynamic tumor therapy, paving the new way for exploring other 2D metal phosphorus trichalcogenides in biomedicine.

Preclinical Study of Plasmodium Immunotherapy Combined with Radiotherapy for Solid Tumors.

Immune checkpoint blockade therapy (ICB) is ineffective against cold tumors and, although it is effective against some hot tumors, drug resistance can occur. We have developed a Plasmodium immunotherapy (PI) that can overcome these shortcomings. However, the specific killing effect of PI on tumor cells is relatively weak. Radiotherapy (RT) is known to have strong specific lethality to tumor cells. Therefore, we hypothesized that PI combined with RT could produce synergistic antitumor effects. We tested our hypothesis using orthotopic and subcutaneous models of mouse glioma (GL261, a cold tumor) and a subcutaneous model of mouse non-small cell lung cancer (NSCLC, LLC, a hot tumor). Our results showed that, compared with each monotherapy, the combination therapy more significantly inhibited tumor growth and extended the life span of tumor-bearing mice. More importantly, the combination therapy could cure approximately 70 percent of glioma. By analyzing the immune profile of the tumor tissues, we found that the combination therapy was more effective in upregulating the perforin-expressing effector CD8+ T cells and downregulating the myeloid-derived suppressor cells (MDSCs), and was thus more effective in the treatment of cancer. The clinical transformation of PI combined with RT in the treatment of solid tumors, especially glioma, is worthy of expectation.

Abstract P208: Synergistic antitumor activity of lisaftoclax (APG-2575) and alrizomadlin (APG-115) through dual targeting of BCL-2/MDM2-P53 apoptotic pathways in preclinical models of acute myeloid leukemia

Abstract Background: In many hematologic malignancies, BCL-2 is overexpressed and is a viable therapeutic target. In relapsed or refractory acute myeloid leukemia (R/R AML), BCL-2 inhibitor venetoclax as a single agent has limited activity, thereby necessitating combination treatments, some of which are actively under clinical development. In addition, the mutation rate of TP53 is rare in AML, and the frequency of MDM2 overexpression is high, representing an opportunity for pharmacologic intervention of the MDM2-P53 apoptosis pathway. Synergistic effects of MDM2 inhibitor idasanutlin and venetoclax have been reported in preclinical models of TP53 wild-type AML (Pan et al, Cancer Cell 2017). Lisaftoclax (APG-2575) and alrizomadlin (APG-115) are novel BCL-2 and MDM2 inhibitors, respectively. They show unique pharmacological properties as well as clinical activity and tolerable safety profiles in patients with hematologic or solid malignancies (Tolcher et al, J Clin Oncol 2021:2506; Ailawadhi et al, J Clin Oncol 2021:7502). Here, we examined the effects of combined lisaftoclax and alrizomadlin in preclinical models of AML. Materials and Methods: AML cell lines and mouse xenograft models were employed. Antiproliferative activity was measured by CellTiter-Glo luminescent cell viability assay. Apoptosis was evaluated by annexin V/propidium iodide staining and flow cytometry. Meso-Scale Discovery ELISA assay and western blot analyses were used to characterize the mechanisms of the synergistic effects of this combination. In animal studies, clinically relevant doses of lisaftoclax were employed. A pulsed high-dose regimen of alrizomadlin was used to achieve best efficacy and manage on-target toxicity. Results: In TP53 wild-type AML cell lines MOLM-13, MV-4-11, and OCI-AML-3, both single-agent lisaftoclax and alrizomadlin exerted apoptogenic activity. The combination had synergistic apoptogenic and antiproliferative activity. In subcutaneous xenograft models derived from MV-4-11 and OCI-AML-3 cells, the combination substantially inhibited tumor growth relative to the impact observed with either single agent. In a systemic xenograft model derived from MOLM-13 cells, the combination significantly (P < .05) extended the life span of tumor-bearing mice by 135% to 237% compared to that of tumor-bearing mice treated with lisaftoclax or alrizomadlin alone, which resulted in extensions of 4% to 26% and 41% to 95%, respectively. Synergistic anti-leukemic activity was confirmed in a patient-derived systemic AML model. Mechanistically, the combination synergistically downregulated anti-apoptotic proteins MCL-1 and BCL-xL and primed AML cells to apoptosis induced by lisaftoclax. Conclusions: We show a significant synergy of lisaftoclax and alrizomadlin and novel mechanisms associated with the combination of these agents in preclinical models of TP53 wild-type AML. These data support investigation into the clinical outcomes of the combination treatment in patients with TP53 wild-type AML. Citation Format: Douglas D. Fang, Qiuqiong Tang, Qixin Wang, Na Li, Feng Zhou, Guoqin Zhai, Yan Yin, Dajun Yang, Yifan Zhai. Synergistic antitumor activity of lisaftoclax (APG-2575) and alrizomadlin (APG-115) through dual targeting of BCL-2/MDM2-P53 apoptotic pathways in preclinical models of acute myeloid leukemia [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P208.

Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis.

Pseudouridine is the most frequent epitranscriptomic modification. However, its cellular functions remain largely unknown. Here we show that the pseudouridine synthase PUS7 is highly expressed in glioblastoma versus normal brain tissues, and high PUS7 expression levels are associated with worse survival in glioblastoma patients. The PUS7 expression and catalytic activity are required for glioblastoma stem cell (GSC) tumorigenesis. Mechanistically, we identified PUS7 targets in GSCs through small RNA pseudouridine sequencing, and showed that pseudouridylation of PUS7-regulated tRNA is critical for codon-specific translational control of key regulators of GSCs. Moreover, we identified chemical inhibitors for PUS7, and showed that these compounds prevented PUS7-mediated pseudouridine modification, suppressed tumorigenesis, and extended lifespan of tumor-bearing mice. Overall, we identified an epitranscriptomic regulatory mechanism in glioblastoma and provided preclinical evidence of a potential therapeutic strategy for glioblastoma.

Evaluation of anticarcinogenic and antioxidant properties of Eruca sativa extracts versus Ehrlich ascites carcinoma in mice

ObjectiveCancer is a major public health issue and characterized by wild cell growth and proliferative disorder. The antitumor and antioxidant role of Eruca sativa (ES) was investigated in a Ehrlich ascites carcinoma (EAC) tumor model in mice. MethodsTwenty-four hours after EAC intraperitoneal inoculation in mice, ES extracts were administered at doses of 250 mg/kg/body weight (BW) for 9 days. Half of the mice were sacrificed on the 10th day for estimation of hematological profiles, red blood cell count, hemoglobin content, packed cell volume, mean corpuscular volume and mean corpuscular hemoglobin. In addition, antioxidant parameters (superoxide dismutase, catalase, and glutathione peroxidase) were evaluated. The remaining mice were kept alive to assess the increase in life span. Aspartate aminotransferase, alanine transaminase, alkaline phosphatase, creatinine, and urea levels were assessed for ES antitumor effects. Results.Oral supplementation of ES seed and leaf extracts significantly reduced tumor parameters such as tumor volume and tumor weight with remarkable enhance in tumor inhibition ratio, vice versa, increased both survival and average BW of tumor-bearing mice. ES extracts significantly increased BW and extended the life span of tumor-bearing mice. Hematological profiles were restored to normal and modulated the abovementioned antioxidant parameters in ES-treated mice compared with EAC control. ConclusionThe current study noticeably demonstrates the antitumor activity of ES seed and leaf extracts significantly prolonged life span and normalized the hematological profiles and biochemical parameters compared with EAC mice.

Phytofabrication of cupric oxide nanoparticles using Simarouba glauca and Celastrus paniculatus extracts and their enhanced apoptotic inducing and anticancer effects

Cupric oxide nanoparticles (CuO NPs) were phytofabricated utilizing leaf extract of Simarouba glauca and aerial extract of Celastrus paniculatus and are considered to hold excellent anticancer capability. Synthesized CuO NPs were characterized for their morphology, crystallinity, and structure. The presence of functional groups of phytochemicals on synthesized nanoparticles was validated by Fourier transform infrared spectroscopy (FTIR) analysis. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) examination reveal the uniform distribution of particles and the average particle size is 35 nm. The anticancer activities on MCF-7 and HT-29 cell lines revealed that CuO NPs synthesized using leaf extract of S. glauca (CuO-SG) induced cell death with half-maximal inhibitory concentration (IC50) value of 107.56 µg/mL and 208.57 µg/mL, while CuO NPs synthesized using the aerial extract of C. paniculatus (CuO-CP) indicated IC50 values of 97.39 µg/mL and 205.11 µg/mL, respectively. To be more precise for anti-cancerous effect, the molecular mechanism was examined in MCF-7 cell line treated with CuO-CP NPs by cell cycle analysis that depicted 75.28% of cell arrest in Sub G0/G1 phase and 71.29% of cells were gated in the late apoptotic phase of Annexin V and propidium iodide (PI) compared to control cells. The present work reports in vivo antitumor studies of CuO-CP NPs against Ehrlich ascites carcinoma (EAC) bearing C57 mice for the first time and was examined by variations in growth parameters, biochemical assays, hematological profile, and histopathological analysis. CuO-CP NPs could eliminate oxidants like lactoperoxidase and myeloperoxidase, stimulate reduced glutathione, restore the hematological profile and increase the life span of tumor-bearing mice treated by them in comparison with control.

Anticancer Potential of Michelia champaca Linn. Bark Against Ehrlich Ascites Carcinoma (EAC) Cells in Swiss Albino Mice

Background: Adverse side effects of currently available therapies against cancer, leads scientists to find effective compounds from natural sources. Objective: In the present study, stem-bark of Mycelia champaca is subjected to evaluate its antiproliferative effect against Ehrlich Ascites Carcinoma (EAC) cells. To date, the anti-proliferative effects of M. champaca bark extract against EAC cell line has not been reported elsewhere. Therefore, we intended to investigate the anti-proliferative potential of M. champaca bark extract against EAC cells in vivo. Methods: In vivo anticancer activity was evaluated against EAC cells bearing Swiss albino mice by monitoring parameters such as tumor cell proliferation, tumor weight measurement, and survival time, etc. The mechanism of EAC killing was examined by observation of cell morphology and analysis the expression of certain cancer-related genes. In vitro antioxidant potentiality was determined in terms of several common antioxidant assays. In addition, total phenolic and flavonoids contents were measured to ensure the presence of phytochemicals. Results: M. champaca bark extract showed strong antioxidant activities which were found to be strongly correlated (P<0.001) with phenolics and flavonoids contents. Furthermore, it was found that bark extract decreased tumor cell proliferation (77.46%; P<0.01), tumor weight (42.13%; P<0.001) and increased life span of tumor-bearing mice (71.97%; P<0.01) at the dose of 250mg/kg (intraperitoneal; i.p.). M. champaca bark also altered the depleted hematological parameters such as red blood cell, white blood cell, hemoglobin (Hb%) towards normal in tumor bearing mice. In addition, upregulation of p53, Bax and downregulation of Bcl-2 followed by treatment indicated M. champaca bark could induce apoptosis of EAC cells. Conclusion: These results indicated that MEMCB possesses significant cytotoxic activities against EAC cells and has a strong in vitro antioxidant capacity. Therefore, the bark of M. champaca could be considered as a potential resource of anti-cancer agents, which might be used to formulate effective anticancer drugs.

Therapeutic potential of xanthones from Swertia chirata in breast cancer cells.

Background & objectives:Medicinal plants like Swertia chirata are rich sources of different xanthones. This study was aimed to assess the cytotoxic potential of four most abundant xanthones present in S. chirata both in vivo and in vitro in Ehrlich ascites carcinoma (EAC), a mouse transplantable breast carcinoma cell line and two human breast carcinoma cell lines (MCF-7 and MDA-MB-231).Methods:Four xanthones derived from S. chirata namely 1-hydroxy-3,7,8-trimethoxyxanthone (XA), 1,8-dihydroxy-3,5-dimethoxyxanthone (XB), 1-hydroxy-3,5,8-trimethoxyxanthone (XC) and 1,5,8-trihydroxy-3-methoxyxanthone (XD) were used for determination of sub-lethal dose on the cell lines EAC, MCF-7, MDA-MB-231 and verified toxicity of sub-lethal dose on normal murine fibroblast cells. Cytotoxicity was measured in vivo and survivability of mice was plotted accordingly. Therapeutic efficacy of XD was evaluated both in vivo and in vitro by determination of lipid peroxidation (LPO), reactive oxygen species (ROS) generation and by quantitating the enzyme status (GSH, catalase, superoxide dismutase) in treated and untreated samples. DNA damage was evaluated using comet and DNA fragmentation assays. Furthermore, apoptotic effect was analyzed by flow cytometry and validated by TUNEL assay and Western blotting.Results:Among all the xanthones tested XD showed IC50 at the lowest dose, and normal cells were unaffected at this dose. Survivability of mice increased significantly when treated with XD compared to other xanthones and cisplatin. Significantly increased ROS and LPO were found in cancer cells as a result of XD treatment which was unaltered in normal cell line. XD induced DNA damage and apoptosis in cancer cell lines.Interpretation & conclusions:Our experimental data indicate that XD may potentially act as a chemotherapeutic agent by enhancing ROS in breast cancer cells thereby leading to apoptosis.

Carboxyamidotriazole combined with IDO1-Kyn-AhR pathway inhibitors profoundly enhances cancer immunotherapy

BackgroundCancer immunotherapy has generated significant excitement, mainly as a result of the development of immune checkpoint inhibitors. The blockade of PD-1 or its ligand with antibodies has resulted in impressive clinical efficacy. However, a subset of patients does not respond to biologic therapeutics, and another subset suffers from severe immune-related adverse events in certain cases. The modulation of the immune system with small molecules might yield surprising benefits.MethodsCD8+ cells were obtained through a magnetic cell sorting system (MACS), and their capabilities for IFN-γ release and PD-1 expression were analyzed. The in vitro effects of drugs were studied in a coculture system of tumor cells and activated CD8+ cells. We further isolated the primary tumor cells in tumor-bearing mice treated with CAI, DMF, 1-MT or a combination (CAI and DMF/CAI and 1-MT) and analyzed the percentages of CD8+ T cells and PD-1+CD8+ T cells among TILs. The selective anti-tumor immune reactions of the two drug combinations were confirmed in a coculture system consisting of B16-OVA cells and OVA-specific CTLs derived from OT-1 transgenic mice. The anti-tumor effects of the single drugs or combined therapies were assessed according to their capability to slow tumor growth and extend the life span of tumor-bearing mice, and they were compared with the effects of PD-1 antibody.ResultsCAI increased IFN-γ release from activated T cells, which might strengthen the anti-proliferative and anti-metastatic effects on cancer cells. However, CAI also stimulated IDO1-Kyn metabolic circuitry in the tumor microenvironment and facilitated tumor cell immune evasion. Combining CAI with 1-MT or DMF disrupted PD-1 expression and promoted IFN-γ production in CD8+ T cells, and it also increased T lymphocyte infiltration in the tumor microenvironment, inhibited tumor growth and prolonged the life spans of tumor-bearing mice.ConclusionInhibitors of the IDO1-Kyn-AhR pathway could abolish the negative effects of CAI on CD8+ T cells and result in complementary and beneficial anti-tumor immune effects. The combination of CAI with 1-MT or DMF greatly augmented the ability of CD8+ T cells to kill malignant cells and showed a strong anti-cancer capability that was superior to that of either of the single agents was is comparable with that of anti-PD-1 antibody. The combinations of small molecules utilized in this study may serve as valuable new immunotherapy strategies for cancer treatment.

Astragalus Polysaccharide RAP Selectively Attenuates Paclitaxel-Induced Cytotoxicity Toward RAW 264.7 Cells by Reversing Cell Cycle Arrest and Apoptosis.

Purpose: The purpose of this study was to determine if an Astragalus polysaccharide (RAP) can protect immune cells from the toxic side effects of paclitaxel (Taxol), a powerful anti-tumor drug whose equally powerful side effects limit its clinical use.Methods: We hypothesized that RAP can reduce the toxic effects induced by Taxol. To test this hypothesis, we conducted a series of studies in vivo and in vitro. First, we confirmed RAP’s effects in vivo utilizing BALB/c mice inoculated with 4T1 mouse breast cancer cells as the tumor model. Mice were treated with RAP and/or Taxol, and the differences in the life spans were recorded. Second, a co-culture cell model was used to study the protective effect of RAP on cells vis-a-vis Taxol. The cell cycle and apoptosis of RAW 264.7 cells that were treated with RAP with/without Taxol were checked by flow cytometry and Hoechst staining. Proteins involved in the cell cycle and apoptosis were also tested by Western blot to reveal the probable mechanism.Results: RAP prolonged the life span of tumor-bearing mice treated with Taxol. The in vitro experiments showed that Taxol suppressed the proliferation of RAW 264.7 cells while RAP protected the RAW 264.7 cells from Taxol-induced suppression. The protection is selective because RAP had no effect on 4T1 cells. Furthermore, Taxol clearly led to cell cycle arrest mainly at the G2/M phase and generated cytotoxicity against RAW 264.7 cells, while RAP blocked cell cycle arrest and protected cells from apoptosis. Taxol up-regulated the protein levels of P-H2A, PARP, Chk1, p53, and p21 and down-regulated Bcl-Xl and Mcl-1, and RAP reversed the expression of all these proteins.Conclusion: These results suggested that RAP can protect immune cells from Taxol-induced toxicity, by changing the cell cycle and apoptosis.

An innovative anti-cancer Chinese herbal formula exhibited multi-targeted efficacies in metastatic breast cancer mouse model

BackgroundThe incidence and mortality of cancer metastasis is high worldwide. Despite of the chemotherapeutic agents, many cancer patients still take traditional Chinese herbal prescriptions as adjuvant treatments. However, most of these herbal formulae/products lack of evidence-based efficacy. Based on our previous investigations on anti-tumor, anti-angiogenic, anti-metastatic, bone protective and immunomodulating activities of various Chinese herbal medicines, four constituent herbs, namely Andrographis paniculata, Acanthopanax senticosus, Camellia sinensis, and Hedyotis diffusa were eventually selected to form an innovative herbal formula.MethodsThe anti-tumor efficacies of the formula were evaluated in metastatic breast cancer mice model. The bone protective and immunomodulatory effects were also assessed after formula treatment.ResultsOur results showed that the breast tumor weight as well as lung and liver metastasis in mice could be reduced after herbal formula treatment for 4 weeks. The breast tumor-induced osteolysis in mice was restored by herbal formula treatment, in which the bone volume in treated mice tibia was comparable to that in the non-tumor bearing normal mice. The IL-12 level was augmented and the survival of mice with metastatic breast tumors was prolonged after treatment. Furthermore, combination of herbal formula with chemotherapeutic agent doxorubicin resulted in better anti-tumor efficacy and increased life span in tumor-bearing mice, when compared with doxorubicin alone treatment.ConclusionsIn summary, our innovative Chinese herbal formula was demonstrated to possess anti-tumor, anti-metastatic and bone-protective activities in metastatic breast tumor-bearing mice. The preclinical data generated in this study would lead to the development of evidence-based supplement as adjuvant therapy for metastatic breast cancer.

Cell Penetrating Capacity and Internalization Mechanisms Used by the Synthetic Peptide CIGB-552 and Its Relationship with Tumor Cell Line Sensitivity.

CIGB-552 is a twenty-amino-acid novel synthetic peptide that has proven to be effective in reducing tumor size and increasing lifespan in tumor-bearing mice. Such capability is conferred by its cell-penetrating peptide character, which allows it to enter cells and elicit a pro-apoptotic effect through its major mediator, COMMD1 protein. Cell-penetrating peptides are able to use different internalization mechanisms, such as endocytosis or direct transduction through the plasma membrane. Although CIGB-552 cytotoxicity has been evaluated in several non-tumor- and tumor-derived cell lines, no data regarding the relationship between cell line sensitivity, cell penetrating capacity, the internalization mechanisms involved, COMMD1 expression levels, or its subcellular localization has yet been produced. Here, we present the results obtained from a comparative analysis of CIGB-552 sensitivity, internalization capacity and the mechanisms involved in three human tumor-derived cell lines from different origins: mammary gland, colon and lung (MCF-7, HT-29 and H460, respectively). Furthermore, cell surface markers relevant for internalization processes such as phosphatidylserine, as well as CIGB-552 target COMMD1 expression/localization, were also evaluated. We found that both endocytosis and transduction are involved in CIGB-552 internalization in the three cell lines evaluated. However, CIGB-552 incorporation efficiency and contribution of each mechanism is cell-line dependent. Finally, sensitivity was directly correlated with high internalization capacity in those cell lines where endocytosis had a major contribution on CIGB-552 internalization.

Enhanced antitumor efficacy of doxorubicin-encapsulated halloysite nanotubes.

To improve the antitumor efficacy of doxorubicin (DOX) and provide novel clinical treatment of gastric cancer, halloysite nanotubes (HNTs) loaded with DOX were encapsulated by soybean phospholipid (LIP) and the formed HNTs/DOX/LIP was systematically characterized via different techniques. The in vitro anticancer activity of HNTs/DOX/LIP was examined using an MTT assay. The antitumor efficacy and biocompatibility were monitored by measuring the tumor volume and assessing the blood routine and serum biochemistry using an ectopic implantation cancer model. The results show that when the concentration of HNTs was 3 mg/mL and the concentration of DOX was 1 mg/mL the optimal DOX loading efficiency was as high as 22.01%±0.43%. In vitro drug release behavior study demonstrated that HNTs/DOX/LIP shows a pH-responsive release property with fast drug release under acidic conditions (pH =5.4). MTT assays and in vivo experimental results revealed that HNTs/DOX/LIP exhibits a significantly higher inhibitory efficacy on the growth of mouse gastric cancer cells than free DOX at the same drug concentration. In addition, the life span of tumor-bearing mice in the HNTs/DOX/LIP-treated group was obviously prolonged compared with the control groups. Moreover, HNTs/DOX/LIP possessed excellent hemocompatibility as shown in the blood and histology studies. These findings indicated that the formed HNTs/DOX/LIP possesses higher antitumor efficacy and may be used as a targeted delivery nanoplatform for targeting therapy of different types of cancer cells.

Andrographolide enhances cisplatin-mediated anticancer effects in lung cancer cells through blockade of autophagy.

Lung cancer is the most common cause of cancer-related death worldwide and the platinum-based drugs such as cisplatin have been used as the first line of the treatment. However, the clinical effectiveness of such chemotherapy is limited by intrinsic or acquired resistance. In this study, we found that cisplatin induced autophagy that attenuated the sensitivity of both A549 and Lewis lung cancer (LLC) cells to cisplatin. In contrast, the clinical drug andrographolide (Andro) suppressed autophagy and enhanced cisplatin-mediated apoptosis in these cells. Using two murine lung cancer models, including a subcutaneously inoculated LLC model and an orthotopic LLC implantation model, we investigated the therapeutic efficacy of the combined treatment of cisplatin and Andro. Compared with the sole cisplatin treatment, combining cisplatin with Andro potentially inhibited tumor growth, reduced the incidence of lung metastases, and relieved renal tubular damage. Moreover, the combined treatment prolonged the life span of tumor-bearing mice. TUNEL and immunohistochemistry assays showed the increase in apoptotic cells and the decrease in both conversion of LC3B-I to LC3B-II and Atg5 protein expression in the tumor tissues from mice with the combined treatment. These results suggest that Andro offers an ideal candidate of autophagy inhibitors in clinical application, and combination of cisplatin with Andro could be a promising strategy for the treatment of lung cancer.

The first report of cases of pet dogs with naturally occurring cancer treated with the antitumor peptide CIGB-552

The absence of an effective therapy against human solid tumors has fostered the development of promising antineoplastic therapeutic candidates, as the CIGB-552 peptide. This synthetic peptide has shown to be effective in reducing tumor size and increasing the lifespan in tumor-bearing mice. Therefore, this work was aimed to explore the safety profile and preliminary assessment of antitumor activity of the CIGB-552 peptide therapeutic candidate in a small population of dogs (n=9) having malignant spontaneously-arising solid tumors. The peptide was administered by subcutaneous (s.c.) route, at three dosage levels (0.075, 0.15 and 0.3mg/kg). The results showed no dose-limiting toxicities in any dogs. The antitumor activity observed in dogs receiving CIGB-552 was associated with the reduction in the tumor volume. Given the antitumor effects of CIGB-552 as mediated by COMMD1 protein, which function is highly conserved among eukaryotic organisms, and the similarities of canine and human types of cancer with respect to tumor biology, it is likely that CIGB-552 could demonstrate comparable anti-cancer activity in human patients.Synthetic peptide, COMMD1, Tumor, Dog, CIGB-552.

Assessment of Cytotoxicity on Moringa Olifera Against Ehrlich Ascites Carcinoma in Swiss Albino Mice

Objective: The present study determines the potent cytotoxic and antitumor properties of methanolic extract of Moringa oleifera leaves.Material and Method: The leaves were collected from in and around Tiruchengode of Nammakal district of Tamilnadu. The collected leaves were shade dried and powdered and the Methanolic extract was extracted using the soxhlet apparatus. In-vitro cytotoxicity study was done by Tryphan Blue Dye Exclusion method and MTT (3-(4, 5-dimethyl thiazolyl-2)-2, 5- diphenyltetrazolium bromide) assay. In short-term cytotoxicity study by Tryphan Blue Dye Exclusion method the IC50 value against EAC cell lines was found to be 163.91 µg/ml. In Long-term cytotoxicity study by MTT assay the IC50 value against Normal Mouse Embryonic Fibroblast (NIH 3T3) was found to be 260.85 µg/ml for Human Cervical Cancer cells (HeLA) was 182.41 µg/ml for Human Laryngeal Epithelial Carcinoma (HeP-2) was 195.93. µg/ml and for Human Liver Cancer cells (HepG2) was 168.61 µg/ml. The MST of the control group was 17.33 ± 1.53 days, whereas it was 43.67 ± 1.15, 23.67 ± 1.53 and 33.33 ± 1.53 days for the groups treated with MMO (200 and 400mg/kg) and 5 FU respectively (0.001 & 0.001). The increase in lifespan of Tumour-bearing mice treated with MMO and 5-FU was found to be 36. 75, 92.78 and 152.84 respectively.Result: Haematological parameters of a tumour bearing mice on the day 14 were showed significant changes when compared to normal mice. The total WBC count, protein and PCV were found to increase with a reduction in the hemoglobin content of RBC. At the same time interval, MMO (200 and 400mg/kg) treatment could change these parameters near normal. Maximum alternation occurred in the MMO treatment at the dose of (400mg/kg). There was the significant reduction in the Tumour volume of mice treated with MMO (200 and 400 mg/kg/p.o.). The Tumour volume of control animals was 2. 92 ± 0.12 ml where it was 2.55 ± 0.11 ml and 1.82 ± 0.04 ml for the groups treated with MMO (200 and 400mg/kg/p.o) respectively (P < 0.01 & 0.005).Coclusion: The present study provides clear evidence, that the extract of Moringa olifera shows effective cytotoxicity against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. A further study about the active principles and mechanism of action of the Methanolic extract of Moringa oleifera at the molecular level was needed.

Cytotoxic Indole Alkaloid 3α-Acetonyltabersonine Induces Glioblastoma Apoptosis via Inhibition of DNA Damage Repair.

Cytotoxic indole alkaloids from Melodinus suaveolens, which belongs to the toxic plant family Apocynaceae, demonstrated impressive antitumor activities in many tumor types, but less application in glioblastoma, which is the lethal brain tumor. In the present study, we reported the anti-glioblastoma activity of an indole alkaloid, 3α-acetonyltabersonine, which was isolated from Melodinus suaveolens. 3α-acetonyltabersonine was cytotoxic to glioblastoma cell lines (U87 and T98G) and stem cells at low concentrations. We verified 3α-acetonyltabersonine could suppress tumor cell proliferation and cause apoptosis in glioblastoma stem cells (GSCs). Moreover, detailed investigation of transcriptome study and Western blotting analysis indicated the mitogen activated protein kinase (MAPK) pathway was activated by phosphorylation upon 3α-acetonyltabersonine treatment. Additionally, we found 3α-acetonyltabersonine inhibited DNA damage repair procedures, the accumulated DNA damage stimulated activation of MAPK pathway and, finally, induced apoptosis. Further evidence was consistently obtained from vivo experiments on glioblastoma mouse model: treatment of 3α-acetonyltabersonine could exert pro-apoptotic function and prolong the life span of tumor-bearing mice. These results in vitro and in vivo suggested that 3α-acetonyltabersonine could be a potential candidate antitumor agent.

Chitosan nanoparticle-based delivery of fused NKG2D-IL-21 gene suppresses colon cancer growth in mice.

Nanoparticles can be loaded with exogenous DNA for the potential expression of cytokines with immune-stimulatory function. NKG2D identifies major histocompatibility complex class I chain-related protein in human and retinoic acid early induced transcript-1 in mouse, which acts as tumor-associated antigens. Biologic agents based on interleukin 21 (IL-21) have displayed antitumor activities through lymphocyte activation. The NKG2D–IL-21 fusion protein theoretically identifies tumor cells through NKG2D moiety and activates T cells through IL-21 moiety. In this study, double-gene fragments that encode the extracellular domains of NKG2D and IL-21 genes were connected and then inserted into the pcDNA3.1(−) plasmid. PcDNA3.1–dsNKG2D–IL-21 plasmid nanoparticles based on chitosan were generated. Tumor cells pretransfected with dsNKG2D–IL-21 gene nanoparticles can activate natural killer (NK) and CD8+ T cells in vitro. Serum IL-21 levels were enhanced in mice intramuscularly injected with the gene nanoparticles. DsNKG2D–IL-21 gene nanoparticles accumulated in tumor tissues after being intravenously injected for ~4–24 h. Treatment of dsNKG2D–IL-21 gene nanoparticles also retarded tumor growth and elongated the life span of tumor-bearing mice by activating NK and T cells in vivo. Thus, the dsNKG2D–IL-21 gene nanoparticles exerted efficient antitumor activities and would be potentially used for tumor therapy.

Worldwide malaria incidence and cancer mortality are inversely associated

BackgroundInvestigations on the effects of malaria infection on cancer mortality are limited except for the incidence of Burkitt’s lymphoma (BL) in African children. Our previous murine lung cancer model study demonstrated that malaria infection significantly inhibited tumor growth and prolonged the life span of tumor-bearing mice. This study aims to assess the possible associations between malaria incidence and human cancer mortality.MethodsWe compiled data on worldwide malaria incidence and age-standardized mortality related to 30 types of cancer in 56 countries for the period 1955–2008, and analyzed their longitudinal correlations by a generalized additive mixed model (GAMM), adjusted for a nonlinear year effect and potential confounders such as country’s income levels, life expectancies and geographical locations.ResultsMalaria incidence was negatively correlated with all-cause cancer mortality, yielding regression coefficients (log scale) of −0.020 (95%CI: −0.027,-0.014) for men (P < 0.001) and-0.020 (95%CI: −0.025,-0.014) for women (P < 0.001). Among the 29 individual types of cancer studied, malaria incidence was negatively correlated with colorectum and anus (men and women), colon (men and women), lung (men), stomach (men), and breast (women) cancer.ConclusionsOur analysis revealed a possible inverse association between malaria incidence and the mortalities of all-cause and some types of solid cancers, which is opposite to the known effect of malaria on the pathogenesis of Burkitt’s lymphoma. Activation of the whole immune system, inhibition of tumor angiogenesis by Plasmodium infection may partially explain why endemic malaria might reduce cancer mortality at the population level.