Antioxidant and Antitumor Activity of Indonesian Herbal Ingredients

The present study was to aimed to evaluated and compare in vitro antioxidant activities of 2 Indonesian herbal ingredients (A and B), determined total phenol content., cytotoxic and apoptosis induction activities on HL-60 cells. These data were providing some useful information for people healthy dietary and the new potential application of natural antioxidant containing food materials in functional foods and also as new cancer therapeutics promising candidates. The parameters were total antioxidant activity, amount of total cytotoxic effect on the growth of human promyelocytic leukemia cells (HL-60). Statistical comparison was perform with Student's t-test at p<0.05. The correlation coefficient (r2) between the parameters tested was established by regression analysis. The scavenging effect of extracts herbal on DPPH radicals increased from 0.3-1.5 mg/ml, where is sample A 14.33% to 64.29% and sample B 9.09% to 57.53% was obtained. High content of total phenol compounds were in sample A (21.72 mg GAE/g), lower amounts were in sample B (17.53 mg GAE/g). Apoptosis of HL-60 cells from the morphological changes side (chromatin condensation). Chromatin condensation, a specific and distinct feature of apoptotic cells, was found in the majority of treated cells. The results indicated that the cell death receptor pathway was involved in the apoptosis induced by Indonesian herbal extracts

Antitumor factors of draining lymph node cells of the mouse sensitized with ehrlich ascites tumor cells. I. Antitumor effect of subcellular factor

The regional lymph node cells of the mice sensitized with Ehrlich ascites tumor cells is known to possess a substance that shows antitumor activity on target cells (JTC-II cells). For the purpose to clarify the localization of this substance the regional lymph node cells from such sensitized mice were treated with trypsin solution of different concentrations (1.0 %, 0.2 %, and 0.01 %), and the tissue culture was carried out with JTC.II cells. As a result it was found that these lymph node cells lost antitumor activity. Next, by the differential contrifugation of these sensitized lymphocytes we obtained F1 fraction (700 g, sediment), F2 (8,500 g sediment), F3 (100,000 g sediment) and F4 (100,000 g supernatant). In the presence of each of these fractions tissue culture was conducted with JTC-II cells as target cells, and it was found that the substance with antitumor activity is contained abundantly in F2 fraction (8,500 g sediment) and F4 fraction (100,000 g supernatant). After giving due consideration to the results of these two experiments and also to the available data in the literature, we assume that the substance with antitumor activity is contained in the cell membrane component.</p

Antitumor activity of an anti-CD98 antibody.

CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors

Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways.

Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy

Antitumor factor of regional lymph node cells in the transplantation of Ehrlich tumor cells. 3. Passive transfer of the antitumor factor

In vitro and in vivo experiments were conducted for the purpose to determine whether or not the antitumor factor found in the regional lymph node cells of the mouse sensitized with Ehrlich tumor cells would transfer its antitumor activity to normal lymph node cells. In in vivo experiments normal lymph node cells incubated at 5°C for 60 minutes in the supernatant containing the antitumor activity have shown the antitumor activity against JTC-11 cells in mixed culture. Namely, it hs been demonstrated that the antitumor activity in the supernatant can be transferred directly to normal lymph node cells in vitro. In the in vitro experiments, the same results as in in vivo experiments were obtained. The antitumor activity against JTC-11 cells has been detected in the lymph node cells obtained on 4, 7 and 9 days after subcutaneous and intraperitoneal injections of the supernatant having antitumor activity. Next, we tried DNase and RNase treatments of the sensitized supernant to observe the transfer factor-like snbstance. The results indicate that, while the passive transfer is possible with the supernatant treated with DNase, it is not with the RNase-treated supernatant. From these findings it is assumed that the factor (in the sensitized supernatant) capable of conferring the antitumor activity is an RNA-dependent substance (or a substance closely associated with RNA) and is probably different from the antitumor factor reported in Parts 1 and 2.</p

Association Between SLFN11 and Antitumor Activity of Trabectedin

Background/Aim: Trabectedin is a DNA-damaging agent and has been approved for the treatment of patients with advanced soft tissue sarcoma. Schlafen 11 (SLFN11) was identified as a dominant determinant of the response to DNA-damaging agents. The aim of the study was to clarify the association between SLFN11 expression and the antitumor activity of trabectedin. Materials and Methods: The antitumor activity of trabectedin was evaluated under different expression levels of SLFN11 regulated by RNA interference and CRISPR-Cas9 systems, and the combined antitumor activity of ataxia telangiectasia and Rad3-related protein kinase (ATR) inhibitor and trabectedin in sarcoma cell lines using in vitro a cell viability assay and in vivo xenograft models. Results: SLFN11-knockdown cell lines had a lower sensitivity to trabectedin, compared to parental cells. ATR inhibitor enhanced the antitumor activity of trabectedin in SLFN11-knockdown cells and in a SLFN11-knockout xenograft model. Conclusion: SLFN11 expression might be a key factor in the antitumor activity of trabectedin

Myeloid suppressor cell depletion augments antitumor activity in lung cancer.

BackgroundMyeloid derived suppressor cells (MDSC) are important regulators of immune responses. We evaluated the mechanistic role of MDSC depletion on antigen presenting cell (APC), NK, T cell activities and therapeutic vaccination responses in murine models of lung cancer.Principal findingsIndividual antibody mediated depletion of MDSC (anti-Gr1 or anti-Ly6G) enhanced the antitumor activity against lung cancer. In comparison to controls, MDSC depletion enhanced the APC activity and increased the frequency and activity of the NK and T cell effectors in the tumor. Compared to controls, the anti-Gr1 or anti-Ly6G treatment led to increased: (i) CD8 T cells, (ii) NK cells, (iii) CD8 T or NK intracytoplasmic expression of IFNγ, perforin and granzyme (iv) CD3 T cells expressing the activation marker CD107a and CXCR3, (v) reduced CD8 T cell IL-10 production in the tumors (vi) reduced tumor angiogenic (VEGF, CXCL2, CXCL5, and Angiopoietin1&amp;2) but enhanced anti-angiogenic (CXCL9 and CXCL10) expression and (vii) reduced tumor staining of endothelial marker Meca 32. Immunocytochemistry of tumor sections showed reduced Gr1 expressing cells with increased CD3 T cell infiltrates in the anti-Gr1 or anti-Ly6G groups. MDSC depletion led to a marked inhibition in tumor growth, enhanced tumor cell apoptosis and reduced migration of the tumors from the primary site to the lung compared to controls. Therapeutic vaccination responses were enhanced in vivo following MDSC depletion with 50% of treated mice completely eradicating established tumors. Treated mice that rejected their primary tumors acquired immunological memory against a secondary tumor challenge. The remaining 50% of mice in this group had 20 fold reductions in tumor burden compared to controls.SignificanceOur data demonstrate that targeting MDSC can improve antitumor immune responses suggesting a broad applicability of combined immune based approaches against cancer. This multifaceted approach may prove useful against tumors where MDSC play a role in tumor immune evasion

In vitro studies on the inhibitory effect of lymphoid cells. II. Antitumor activity of lymphoid cells from spontaneous mammary tumor-bearing mice on the autochthonous primary culture tumor cells

As a step in the elucidation of human cancer immunity we studied antitumor activity of lymphoid cells by conducting a series of cultures using the primary culture of cells from spontaneous mammary cancers from C3H and RIll mice mixed with autochthonous lymphoid cells, and obtained the following results. 1) With 24 mammary tumors obtained from 24 mammary cancer. bearing mice, we prepared 22 suspensions containing sufficient numbers of free tumor cells, and attempted primary culture with them. As a result we were able to attain satisfactory primary culture cells in 18 trials. 2) With each group of the 18 primary culture tumor cells we conducted mixed cultures with autochthonous lymphoid cells (mainly spleen cells) in proportion of 1 : 40, for 48 hours, and counted viable tumor cells after the culture. As a result it was found that in 11 trials the lymphoid cells showed antitumor activity. In the remaining 7 groups of lymphoid cells there could be observed no antitumor activity, but some of them showed tendency to slightly accelerate the growth of tumor cells. 3) On looking at the correlation between the antitumor activity of lymphoid cells and the ratio of tumor weight/body weight, it was revealed that the antitumor activity is greatest when the tumor is around 10% the body weight, and as the tumor grows larger, such antitumor activity disappears. From these results, it may be concluded that even in spontaneous mammary cancer of mouse, autochthonous lymphoid cells exhibit anti. tumor activity on indigenous tumor, and this seems to indicate that cell. mediated immunity has been established.</p

In vitro studies on the inhibitory effect of lymphoid cells. II. Antitumor activity of lymphoid cells from spontaneous mammary tumor-bearing mice on the autochthonous primary culture tumor cells

As a step in the elucidation of human cancer immunity we studied antitumor activity of lymphoid cells by conducting a series of cultures using the primary culture of cells from spontaneous mammary cancers from C3H and RIll mice mixed with autochthonous lymphoid cells, and obtained the following results. 1) With 24 mammary tumors obtained from 24 mammary cancer. bearing mice, we prepared 22 suspensions containing sufficient numbers of free tumor cells, and attempted primary culture with them. As a result we were able to attain satisfactory primary culture cells in 18 trials. 2) With each group of the 18 primary culture tumor cells we conducted mixed cultures with autochthonous lymphoid cells (mainly spleen cells) in proportion of 1 : 40, for 48 hours, and counted viable tumor cells after the culture. As a result it was found that in 11 trials the lymphoid cells showed antitumor activity. In the remaining 7 groups of lymphoid cells there could be observed no antitumor activity, but some of them showed tendency to slightly accelerate the growth of tumor cells. 3) On looking at the correlation between the antitumor activity of lymphoid cells and the ratio of tumor weight/body weight, it was revealed that the antitumor activity is greatest when the tumor is around 10% the body weight, and as the tumor grows larger, such antitumor activity disappears. From these results, it may be concluded that even in spontaneous mammary cancer of mouse, autochthonous lymphoid cells exhibit anti. tumor activity on indigenous tumor, and this seems to indicate that cell. mediated immunity has been established.</p