Destruction Of Malignant Cells Research Articles

Bacterial outer-membrane vesicles promote Vγ9Vδ2 T cell oncolytic activity.

Increasing evidence suggests the immune activation elicited by bacterial outer-membrane vesicles (OMVs) can initiate a potent anti-tumor immunity, facilitating the recognition and destruction of malignant cells. At present the pathways underlying this response remain poorly understood, though a role for innate-like cells such as γδ T cells has been suggested. Peripheral blood mononuclear cells (PBMCs) from healthy donors were co-cultured with E. coli MG1655 Δpal ΔlpxM OMVs and corresponding immune activation studied by cell marker expression and cytokine production. OMV-activated γδ T cells were co-cultured with cancer cell lines to determine cytotoxicity. The vesicles induced a broad inflammatory response with γδ T cells observed as the predominant cell type to proliferate post-OMV challenge. Notably, the majority of γδ T cells were of the Vγ9Vδ2 type, known to respond to both bacterial metabolites and stress markers present on tumor cells. We observed robust cytolytic activity of Vγ9Vδ2 T cells against both breast and leukaemia cell lines (SkBr3 and Nalm6 respectively) after OMV-mediated expansion. Our findings identify for the first time, that OMV-challenge stimulates the expansion of Vγ9Vδ2 T cells which subsequently present anti-tumor capabilities. We propose that OMV-mediated immune activation leverages the anti-microbial/anti-tumor capacity of Vγ9Vδ2 T cells, an axis amenable for improved future therapeutics.

Abstract 1232: Using mesoporous silica nanoparticles (MSNs) for delivering the mesoionic compound MIH 2.4Bl in treating breast cancer

Abstract Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women worldwide, accounting for approximately 24% of all new cancer cases and is the leading cause of cancer death in over 100 countries. Thus, breast cancer is one of the most critical public health problems in the world facing women. There is a growing interest in studying the biological activity of mesoionic compounds, which possesses a 5-membered heterocyclic aromatic ring associated with a sextet of electrons. Mesoionic compounds have shown promising potential as anti-cancer agents due to their unique structure and reaction properties. We reported the synthesis of a new 1,3-thiazolium-5-thiolate derivative of a mesoionic compound (MIH 2.4Bl) and the characterization of its selective cytotoxicity on a panel of breast cancer cells lines. The results of our studies suggest a possible induction of apoptotic death through mitochondrial dysfunction by the treatment with MIH 2.4Bl. Based on our previous findings, MIH 2.4Bl is a promising candidate for treating breast cancer. However, a major challenge facing cancer therapy is the selective destruction of malignant cells while sparing normal cells to preserve tissue integrity. The development and use of drug delivery systems is a recognized approach to improve the efficacy of chemotherapy agents. Nonetheless, drug delivery systems have been unexplored in the context of mesoionic compounds. Drug delivery based on nanotechnology has flourished as a platform applicable to cancer therapy. Among various types of nanoparticles, mesoporous silica nanoparticles (MSNs) are more attractive nanomaterials for a broad range of functionality including gene/drug delivery, cancer therapy and bioimaging due to their broad surface area, less toxicity, low density, excellent biocompatibility, higher drug loading capacity, and impressive mechanical and thermal stability. In this preliminary work, we present an improved delivery strategy of a newly developed formulation of MIH 2.4BI compound with MSNs as the delivery agent. Also, physico-chemical characterization of the nanoparticles and cytotoxicity analyses using a panel of breast cancer cell lines were performed. These studies support the potential therapeutic use of MIH 2.4Bl in treating breast cancer. Citation Format: Dipti Debnath, Sami Nazzal, Suchismita Acharya, Helivaldo Diógenes da Silva Souza, Petrônio Filgueiras de Athayde Filho, Rafal Fudala, J Michael Mathis. Using mesoporous silica nanoparticles (MSNs) for delivering the mesoionic compound MIH 2.4Bl in treating breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1232.

Abstract 300: An improved strategy for delivering the mesoionic compound MIH 2.4Bl utilizing reconstituted high density nanoparticles (rHDL) in treating breast cancer

Abstract Based on data from the World Health Organization, breast cancer is the most common type of cancer among women, accounting for about 15% of all cancer-related deaths. Thus, new treatment options are urgently needed to decrease this mortality rate. In recent years, mesoionic compounds have shown promising potential as anti-cancer agents due to their unique structure and reaction properties. We recently reported that a 1,3-thiazolium-5-thiolate mesoionic compound (MIH 2.4Bl) inhibited oxidative phosphorylation in the MCF-7 breast cancer cell line compared to normal human mammary epithelial cells. Furthermore, MIH 2.4Bl induced cytotoxicity by activating autography-related proteins (Beclin-1 and ATG5) and cell cycle arrest at the G2/M phase. Based on our previous findings, MIH 2.4BI is a promising candidate for treating breast cancer. However, a major challenge facing cancer therapeutics is tumor delivery in vivo for the selective destruction of malignant cells while sparing normal cells to preserve tissue integrity. The development and use of drug delivery systems is a recognized approach to improve the efficacy of chemotherapy agents. Nonetheless, drug delivery systems have been largely unexplored in the context of mesoionic compounds. Lipoproteins are ideal for carrying transporting lipophilic anti-cancer drugs and imaging agents as they circulate in the bloodstream for an extended period. In addition, the hydrophobic core of lipoprotein particles allows the incorporation of lipophilic components (including a number of anti-cancer agents). Reconstituted high-density lipoprotein (rHDL) mimics the structure and function of endogenous (i.e., human plasma) HDL and thus presents a potentially markedly improved therapeutic strategy for cancer drug delivery. Previous studies from our group have shown that a stable reconstituted synthetic rHDL-drug complex could be prepared by combining paclitaxel and other chemotherapy drugs using the natural lipid and protein components of circulating HDL via a novel procedure. In this preliminary work, we present an improved strategy of using a newly developed formulation of MIH 2.4BI compound with rHDL nanoparticles as the delivery agent. Also, physico-chemical characterization of the nanoparticles and cytotoxicity analyses using a panel of breast cancer cell lines were performed. These studies support the potential therapeutic use of MIH 2.4Bl in treating breast cancer. (D. Debnath and R.M. Petty contributed equally to this work) Citation Format: Dipti Debnath, R. Max Petty, Nirupama Sabnis, Jinmin Zhang, Andras G. Lacko, Helivaldo Diógenes Souza, Petrônio Filgueiras Filho, J. Michael Mathis, Rafal Fudala. An improved strategy for delivering the mesoionic compound MIH 2.4Bl utilizing reconstituted high density nanoparticles (rHDL) in treating breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 300.

Tweaking α -Galactoceramides: Probing the Dynamical Mechanisms of Improved Recognition for Invariant Natural Killer T-cell Receptor in Cancer Immunotherapeutics.

The last few decades have witnessed groundbreaking research geared towards immune surveillance mechanisms and have yielded significant improvements in the field of cancer immunotherapy. This approach narrows down on the development of therapeutic agents that either activate or enhance the recognitive function of the immune system to facilitate the destruction of malignant cells. The α -galactosylceramide derivative, KRN7000, is an immunotherapeutic agent that has gained attention due to its pharmacological ability to activate CD1d-restricted invariant natural killer T(iNKT) cells with notable potency against cancer cells in mouse models; a therapeutic success was not well replicated in human models. Dual structural modification of KRN7000 entailing the incorporation of hydrocinnamoyl ester on C6" and C4-OH truncation of the sphingoid base led to the development of AH10-7 which, interestingly, exhibited high potency in human cells. Therefore, to gain molecular insights into the structural dynamics and selective mechanisms of AH10-7 for human variants, we employed integrative molecular dynamics simulations and thermodynamic calculations to investigate the inhibitory activities of KRN7000 andAH10-7 on hTCR-CD1d towards activating iNKT. Interestingly, our findings revealed that AH10-7 exhibited higher affinity binding and structural effects on hTCR-CD1d, as mediated by the incorporated hydrocinnamoyl ester moiety which accounted for stronger intermolecular interactions with 'non-common' binding site residues. Findings extracted from this study further reveal important molecular and structural perspectives that could aid in the design of novel α-GalCer derivatives for cancer immunotherapeutics.

HLA A24 Associated Tumor Immunity in HER2/neu Positive Breast Cancer

Breast carcinoma is the most common tumor in women and it has resulted in significant morbidity and mortality. Recognition of tumor-associated antigens (TAA) by HLA class I-restricted CD8+ T cells is fundamental for the detection and destruction of malignant cells. HLA A24 has been shown to be associated with presenting peptides in breast carcinoma, which can be targeted for cancer immunotherapy. Overexpression of the HER2 receptor tyrosine kinase is associated with more advanced-stage disease at presentation and a rapidly progressive clinical course. Here we present a case of a 57-year-old female, who presented with a left breast lump. On histopathological examination, diagnosis of infiltrating ductal carcinoma was made . The patient had ER, PR negative and HER/neu positive cancer with nodal metastasis to supraclavicular lymph nodes. Course of Antracycline-based chemotherapy was started. Patient showed no signs of recurrence till the time of writing the article.

Radioprotectors in radiotherapy - advances in the potential application of phytochemicals.

Radiotherapy, in addition to chemotherapy, is currently the primary method of cancer treatment based on destruction of malignant cells by ionizing radiation. Unfortunately, it also affects normal cells, which is associated with negative consequences for a patient. Radioprotectors are compounds used to prevent/protect the non-tumor cells from the harmful effects of radiation. To play their role these compounds should meet several criteria; among others, they should significantly protect normal cells from radiation without changing the tumor cell radiosensitivity. In general, agents used to alter normal tissue toxicity from radiation can be broadly divided into three categories based on timing of delivery in relation to radiation: chemical radioprotectors, mitigators, and treatment. These groups include a diverse range of synthetic compounds in terms of their structure and protective mechanisms. The aminoradiothiol amifostine is the only radioprotectant approved in clinical application. However, its use is limited due to toxicity concerns (it may cause hypotension). Natural compounds, derived from plants, meet all criteria of the ideal radioprotector. They exert their protective actions against adverse effects of ionizing radiation by several mechanisms. Plant compounds that show radioprotective activity include flavonoids and phenolic acids, stilbenes, lycopene, alkaloids, peptides, polysaccharides, and phytohormones. Garlic, green tea, apples, citrus, and ginger are examples of constituents of the human diet that contain radioprotective substances.

Medical nanorobotics: Biotechnology or nanoengeneering?

Nanomedicine: Does this term more than pseudo-scientific “pink of fashio”, at least potentially? From a classical point of view, the goal of nanomedicine is the creation of nanoscale autonomous technical devices (nanobots), programmed to perform diagnostic and/or therapeutic manipulation in a living organism: the destruction of malignant cells, destruction of atherosclerotic plaques, and so on. The main advocate is a point of view (technocratic) on the subject of nanomedicine which is controversial, and its feasibility is questionable. Furthermore, most importantly, the question arises – WHY develop and create wonders of engineering – technical nanoscale devices for correction of the condition of the body, if they have already devised and are effectively being used by biological systems? Does it make sense to reinvent the wheel if it has already been invented and produced by nature, even if called differently? Is it not better, instead of inventing another bike, to focus efforts and resources on understanding the principles of functioning of the natural nanodevices, as well as practicing ways to improve efficiency (optimization) of their functioning in vivo ? Key words : Nanomedicine, Biomolecules, Technic deviced, Auto-antibodies, Health state, Diagnostic, Correction

Dendritic cell immunotherapy for brain tumors.

Glioblastomas are characterized by immunosuppression, rapid proliferation, angiogenesis, and invasion into the surrounding brain parenchyma. Limitations in current therapeutic approaches have spurred the development of personalized, patient-specific treatments. Among these, active immunotherapy has emerged as a viable option for glioma treatment. The ability to generate an immune response utilizing patient-derived dendritic cells (DCs) (professional antigen-presenting cells) is especially attractive. This approach to glioma treatment allows for the immunologic targeting and destruction of malignant cells. Data acquired in multiple pre-clinical models and clinical trials have shown significant responses and prolonged survival. Here we provide an overview of the current status of DC vaccination for the treatment of gliomas.

Cytokines in Graft-versus-Host Disease.

Graft-versus-host disease (GVHD) is a complication of allogeneic bone marrow transplantation whereby transplanted naive and marrow-derived T cells damage recipient tissue through similar mechanisms to those that allow destruction of malignant cells, the therapeutic intent of bone marrow transplantation. The manifestations and severity of GVHD are highly variable and are influenced by the proportions of naive cells maturing along regulatory T cell, Th1, Th2, or Th17 phenotypes. This maturation is largely influenced by local cytokines, which, in turn, activate transcription factors and drive development toward a dominant phenotype. In addition, proinflammatory cytokines exert direct effects on GVHD target tissues. Our knowledge of the role that cytokines play in orchestrating GVHD is expanding rapidly and parallels other infective and inflammatory conditions in which a predominant T cell signature is causative of pathology. Because a broad spectrum of cytokine therapies is now routinely used in clinical practice, they are increasingly relevant to transplant medicine.

Selective intracellular free radical generation against cancer cells by bioactivation of low-dose artesunate with a functionalized mesoporous silica nanosystem.

Excessive free radicals are noxious for living organisms and lead to cell death. Destruction of malignant cells by reactive free radicals has been widely used in cancer treatment. A key consideration is how to allow targeted free radical attack on cancer cells and avoid unwanted side-effects. Herein, we develop an efficient intracellular free radical generation strategy against cancer cells by delivering active ingredients into cancer cells, where free radicals are selectively generated by a lysosomal bioactivation process. Artesunate (ART), which is non-toxic to normal cells, was chosen as the free radical source and transported into cells with a hollow mesoporous silica-based delivery system (ART@HMS). To selectively activate the ART@HMS inside cancer cells, a high-bioactive Fe/O cluster-mesoporous silica nanosystem (Fe/O-MSN) was elaborately prepared. Under the bioactivation of the lysosome, the low-dose ART@HMS together with biocompatible Fe/O-MSN induced significant intracellular generation of toxic free radicals and efficient death of cancer cells. This selective intracellular free radical generation strategy is encouraging for its development into an effective low-cost cancer therapy.

ChemInform Abstract: β‐Glucuronidase‐Responsive Prodrugs for Selective Cancer Chemotherapy: An Update

AbstractReview: 136 refs.

β-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: An update

The design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues is one of the major challenges in medicinal chemistry. In this context, the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase present at high concentration in the microenvironment of most solid tumors has attracted considerable attention. This review summarizes the major progresses that have been realized in this field over the past ten years. This includes the new prodrugs that have been designed to target a wide variety of anticancer drugs, the prodrugs employed in the course of a combined therapy, the dendritic glucuronide prodrugs and the concept of β-glucuronidase-responsive albumin binding prodrugs.

Targeting HLA class I expression to increase tumor immunogenicity

The dynamic interaction between the host immune system and growing cancer has been of central interest to the field of tumor immunology over the past years. Recognition of tumor-associated antigens (TAA) by self-HLA (human leukocyte antigen) class I-restricted CD8+ T cells is a main feature in the detection and destruction of malignant cells. The discovery and molecular characterization of TAA has changed the field of cancer treatment and introduced a new era of cancer immunotherapy aimed at increasing tumor immunogenicity and T-cell-mediated anti-tumor immunity. Unfortunately, while these new protocols of cancer immunotherapy are mediating induction of tumor-specific T lymphocytes in patients with certain malignancies, they have not yet delivered substantial clinical benefits, such as induction of tumor regression or increased disease-free survival. It has become apparent that lack of tumor rejection is the result of immune selection and escape by tumor cells that develop low immunogenic phenotypes. Substantial experimental data support the existence of a variety of different mechanisms involved in the tumor escape phase, including loss or downregulation of HLA class I antigens. These alterations could be caused by regulatory ('soft') or by structural/irreversible ('hard') defects. On the basis of the evidence obtained from experimental mouse cancer models and metastatic human tumors, the structural defects underlying HLA class I loss may have profound implications on T-cell-mediated tumor rejection and ultimately on the outcome of cancer immunotherapy. Strategies to overcome this obstacle, including gene therapy to recover normal expression of HLA class I genes, require consideration. In this review, we outline the importance of monitoring and correction of HLA class I alterations during cancer development and immunotherapy.

Synthesis of Novel C12-Nonmethylated Chlorophyll Derivatives from Methyl Pyropheophorbide-a by Allomerization and Functionalization

Chemical Research Center, Hungarian Academy of Sciences, Budapest 1025, Pusztaszerj ut 59-67, HungaryReceived June 13, 2011, Accepted July 16, 2011Key Words : Pyropheophorbide-a, Chlorophyll, Chlorin, Allomerization, Formylation, FunctionalizationThe major challenge in cancer therapy is the destruction ofmalignant cells while sparing the normal tissues. Amongvarious choices for cancer treatment, photodynamic therapy(PDT) has a unique place and being noninvasive in naturemakes it an increasingly desirable option. PDT is nowwidespread and is used clinically for treating various kindscancers.

PI3K Links NKG2D Signaling to a CrkL Pathway Involved in Natural Killer Cell Adhesion, Polarity, and Granule Secretion

The NK cell-activating receptor NKG2D plays a critical role in the destruction of malignant cells, but many of the cell-signaling mechanisms governing NKG2D-mediated cellular cytotoxicity are unknown. We have identified an NKG2D-mediated signaling pathway that governs both conjugate formation and cytotoxic granule polarization. We demonstrate that an interaction between the regulatory subunit of PI3K, p85, and the adaptor protein CrkL is required for efficient NKG2D-mediated cellular cytotoxicity. We show decreased NK cell-target cell conjugate formation in NK cells treated with PI3K inhibitors or depleted of CrkL. Independent of adhesion, we find that microtubule organization center polarization toward target cells expressing the NKG2D ligand MICA or toward anti-NKG2D-coated beads is impaired in the absence of CrkL. Ab-stimulated granule release is also impaired in NK cells depleted of CrkL. Furthermore, our data indicate that the small Ras family GTPase Rap1 is activated downstream of NKG2D engagement in a PI3K- and CrkL-dependent manner and is required for conjugate formation, MTOC (microtubule organizing center) polarization, and NKG2D-dependent cellular cytotoxicity. Taken together, our data identify an NKG2D-activated signaling pathway that collectively orchestrates NK cell adhesion, cell polarization, and granule release.

PI3-Kinase Links NKG2D Signaling to a CrkL Pathway Involved in Natural Killer Cell Adhesion, Polarity, and Granule Secretion (134.3)

Abstract The NK cell activating receptor NKG2D plays a critical role in the destruction of malignant cells, but many of the cell-signaling mechanisms governing NKG2D-mediated cellular cytotoxicity are unknown. We have identified an NKG2D-mediated signaling pathway that governs both conjugate formation and cytotoxic granule polarization. We demonstrate that an interaction between the regulatory subunit of PI3K, p85, and the adaptor protein CrkL is required for efficient NKG2D-mediated cellular cytotoxicity. We show decreased NK cell - target cell conjugate formation in NK cells treated with PI3K inhibitors or depleted of CrkL. Independent of adhesion, we find that microtubule organization center polarization toward target cells expressing the NKG2D ligand MICA or toward anti-NKG2D coated beads is impaired in the absence of CrkL. Antibody-stimulated granule release is also impaired in NK cells depleted of CrkL. Furthermore, our data indicate that the small Ras-family GTPase Rap1 is required for NK cell killing and is activated downstream of NKG2D engagement in a PI3K- and CrkL-dependent manner. Taken together, our data identify an NKG2D-activated signaling pathway that collectively orchestrates NK cell adhesion, cell polarization and granule release.

Antibody-based cancer therapy

Background: The clinical efficacy of mAbs is generally ascribed to interference with signaling pathways leading to arrest of cell-cycle progression and inhibition of tumor growth. Furthermore, mAbs also have the capacity to activate effector functions of the innate immune system and facilitate the destruction of malignant cells. Objectives: The induction of tumor-specific immunity is a desired outcome in cancer immunotherapy. The prevailing situation raises one major question that has to be addressed. This is the clear need for the induction of tumor-specific immunity by combining mAb treatment with other modalities of cancer immunotherapy. Methods: Through mAb treatment, recent efforts focus at initiating or enhancing active antitumor immune responses by i) potentiating co-stimulation and blocking co-inhibition; and ii) rendering tumors more immunogenic through increased tumor peptide expression. Results/conclusions: In this review, the functional characteristics of mAbs, together with their mechanisms of action and clinical application, is summarized as is the potential of combination immunotherapies using mAbs for the augmentation of adaptive antitumor immunity. The results from preclinical and clinical studies demonstrate that mAbs can also promote tumor-specific active immunity.

Tumor Lysis Syndrome in Lymphoblastic Crisis of CML

Tumor lysis syndrome (TLS) defines the metabolic derangements that occur with tumor breakdown following the initiation of cytotoxic therapy. TLS results from the rapid destruction of malignant cells and the abrupt release of intracellular materials and their metabolites into the extracellular space. The syndrome causes hyperuricemia, hyperkalemia, hyperphosphatemia, secondary hypocalcemia and uremia. It can result in acute renal failure and be fatal. Early recognition of patient at risk and preventive measures are important. There is a high incidence of TLS in tumors with high proliferative rates and large burden such as acute lymphoblastic leukemia and Burkitt's lymphoma. It less commonly occurs in solid tumors such as testicular cancer, breast cancer and small cell lung cancer. There are only a few reports on TLS complicated in CML in blast crisis. So we report a 45-yr-old woman presenting with TLS associated with CML in lymphoblastic crisis after the initiation of cytotoxic chemotherapy. (Korean J Hematol 2006;41:119-123.)

Thermophysical effects in photodynamic tumor therapy

A mathematical model of temperature modes in photodynamic therapy of brain tumors is suggested. Technological conditions for this therapy under which destruction of malignant cells along with photoprocesses are accompanied by hyperthermal and thermotherapeutic temperatures are determined. The realized possibilities allow one to achieve a higher degree of tumor destruction especially for low-perfusion tumors, with nearby healthy tissue being preserved.

Association of Oral Cancers With Alcohol Consumption: Exploring Mechanisms

Association of Oral Cancers With Alcohol Consumption: Exploring Mechanisms