Selective Destruction Of Tumor Cells Research Articles

Combination of Targeted Therapies for Colorectal Cancer Treatment.

The design of innovative therapeutic strategies enabling the selective destruction of tumor cells while sparing healthy tissues remains highly challenging in cancer therapy. Here, we show that the combination of two targeted therapies, including bevacizumab (Bev), and a β-glucuronidase-responsive albumin-binding prodrug of monomethyl auristatin E (MMAE), is efficient for the treatment of colorectal cancer implanted in mice. This combined therapy produces a therapeutic activity superior to that of the association of FOLFOX and Bev currently used to treat patients with this pathology. The increased anticancer efficacy is due to either a synergistic or an additive effect between Bev and MMAE selectively released from the glucuronide prodrug in the tumor microenvironment. Since numerous drug delivery systems such as antibody-drug conjugates employ MMAE as a cytotoxic payload, this finding may be of great interest for improving their therapeutic index by combining them with Bev, particularly for the therapy of colorectal cancer.

CAR T-Cell Targeting of Macrophage Colony-Stimulating Factor Receptor.

Macrophage colony-stimulating factor receptor (M-CSFR) is found in cells of the mononuclear phagocyte lineage and is aberrantly expressed in a range of tumours, in addition to tumour-associated macrophages. Consequently, a variety of cancer therapies directed against M-CSFR are under development. We set out to engineer chimeric antigen receptors (CARs) that employ the natural ligands of this receptor, namely M-CSF or interleukin (IL)-34, to achieve specificity for M-CSFR-expressing target cells. Both M-CSF and IL-34 bind to overlapping regions of M-CSFR, although affinity of IL-34 is significantly greater than that of M-CSF. Matched second- and third-generation CARs targeted using M-CSF or IL-34 were expressed in human T-cells using the SFG retroviral vector. We found that both M-CSF- and IL-34-containing CARs enable T-cells to mediate selective destruction of tumour cells that express enforced or endogenous M-CSFR, accompanied by production of both IL-2 and interferon (IFN)-γ. Although they contain an additional co-stimulatory module, third-generation CARs did not outperform second-generation CARs. M-CSF-containing CARs mediated enhanced cytokine production and cytolytic activity compared to IL-34-containing CARs. These data demonstrate the feasibility of targeting M-CSFR using ligand-based CARs and raise the possibility that the low picomolar affinity of IL-34 for M-CSFR is detrimental to CAR function.

ASSESSMENT OF THE EFFECT OF BORON NEUTRON CAPTURE THERAPY ON TUMOR CELL LINES AND PRIMARY EMBRYONIC CELL CULTURE

Introduction. Boron neutron capture therapy (bnct) is a promising method for treating tumors, in particular, infiltrative malignant tumors, due to the selective destruction of tumor cells without damaging the surrounding normal tissues. This type of therapy is based on nuclear reaction of neutron capture by stable 10b isotope. For the successful implementation of bnct, boron delivery drugs that must be selectively accumulated in malignant cells in a sufficient amount, and a neutron source with the energy required for the neutron capture reaction are needed. At the budker institute of nuclear physics, the accelerator-based neutron source was designed with flux parameters allowing studies on bnct to be conducted.Objective: to assess the effect of bnct on tumor and normal cell lines using borphenylalanine (bpa), borcaptate (bsh) and liposomal borcaptat as boron delivery drugs.Materials and methods. Human cell cultures: glioblastoma (u87), colorectal human adenocarcinoma (sw-620), human melanoma (sk-mel28) and primary embryonic cell lines were irradiated with a neutron flux at the presence of bpa, bsh and liposomal bsh with a concentration of 10b 40 μg/ml. The short-term cytotoxic effect of irradiation was evaluated using trypan blue. Cell survival 96 hours after irradiation was determined using mtt test, and survival fraction was evaluated using the clonogenic test.Results. Early cytotoxic effects of irradiation were not observed for all 4 cell lines. According to mtt and clonogenic tests, the most pronounced effect of bnct was noticed for sw-620 and u87 lines, regardless of boron delivery drug used. For sk-mel28 line, the best effect was achieved after irradiation with liposomal borocaptate. For the primary transplanted embryonic line, high toxicity was revealed when bnct was performed with borphenylalanine and borcaptate.Conclusion. The data obtained indicate that the accelerator-based bnct using boron delivery drugs, such as borphenylalanine, borcaptate and liposomal borcaptat, has a positive effect on tumor lines of glioblastoma, colorectal adenocarcinoma and melanoma.

Erratum to: Ablative treatment options for locally advanced unresectable and borderline resectable pancreatic carcinoma

Background Locally advanced unresectable (nonmetastatic) and borderline resectable pancreatic carcinomas represent a therapeutic challenge. Several minimally invasive local ablative techniques are available for local treatment in these situations. Objective Which interventional techniques and application options are currently available for pancreatic carcinoma and which oncological results could be achieved so far? Material and methods An analysis of reviews and studies was carried out. The selection of literature was based on searches in PubMed and the Cochrane library. The studies analyzed were reviews, meta-analyses and original articles mainly from the period between 2013 and 2018. Single case reports were not included in this review. Results Local ablative techniques are performed with various forms of energy and are associated with specific advantages and disadvantages. They have to be individually tailored to the specific patient and situation. Noninvasive thermal ablation with high-intensity focused ultrasound (HIFU) is primarily used for palliative pain relief. Solid tumors are the main indication for thermal necrosis with microwave ablation (MWA) and radiofrequency ablation (RFA). The use of irreversible electroporation (IRE) enables a selective destruction of tumor cells and can be performed in the vicinity of sensitive structures. This technique is applied for primary tumor control and also for accentuation of tumor margins during resection. Conclusion With local ablative techniques an improvement in the quality of life and possibly the prognosis can be achieved in patients with unresectable pancreatic cancer; however, the latter aspect has to be viewed with caution due to a current lack of well-founded data.

Dual-Locking Nanoparticles Disrupt the PD-1/PD-L1 Pathway for Efficient Cancer Immunotherapy.

The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) enzyme, Cas13a, holds great promise in cancer treatment due to its potential for selective destruction of tumor cells via collateral effects after target recognition. However, these collateral effects do not specifically target tumor cells and may cause safety issues when administered systemically. Herein, a dual-locking nanoparticle (DLNP) that can restrict CRISPR/Cas13a activation to tumor tissues is described. DLNP has a core-shell structure, in which the CRISPR/Cas13a system (plasmid DNA, pDNA) is encapsulated inside the core with a dual-responsive polymer layer. This polymer layer endows the DLNP with enhanced stability during blood circulation or in normal tissues and facilitates cellular internalization of the CRISPR/Cas13a system and activation of gene editing upon entry into tumor tissue. After carefully screening and optimizing the CRISPR RNA (crRNA) sequence that targets programmed death-ligand 1 (PD-L1), DLNP demonstrates the effective activation of T-cell-mediated antitumor immunity and the reshaping of immunosuppressive tumor microenvironment (TME) in B16F10-bearing mice, resulting in significantly enhanced antitumor effect and improved survival rate. Further development by replacing the specific crRNA of target genes can potentially make DLNP a universal platform for the rapid development of safe and efficient cancer immunotherapies.

Metronomic photodynamic therapy with 5-aminolevulinic acid induces apoptosis and autophagy in human SW837 colorectal cancer cells

Metronomic photodynamic therapy (mPDT) has emerged as an attractive treatment for the selective destruction of tumor cells by induction of apoptosis. Here, we compared the effects of mPDT and acute photodynamic therapy (aPDT) on human SW837 colorectal cancer (CRC) cells. CRC cells were subjected to mPDT using various exposure durations, concentrations of 5-aminolevulinic acid (ALA), fluence rates and energy densities. The effects were compared with those induced by aPDT. We found that apoptosis and autophagy were earlier induced to a greater extent by mPDT than by the same dose applied as aPDT. The survival rates for mPDT vs. aPDT were 35.2%, 32.4%,27.6%,31.6% vs. 85.7%, 71.1%, 67.8%, 42.1% after 3, 6, 12, and 24 h PDT, respectively. For the same time points, the apoptotic rates for mPDT vs. aPDT were 43.2%, 47.3%, 54.7%, and 50.3% vs. 14.6%, 17.6%, 27.1%, and 53.2%, respectively. mPDT induced a peak rate of autophagy of 20.0% at 3 h, whereas aPDT induced two smaller peaks at 3 h (14.1%) and 12 h (15.8%). Advanced autophagosomes were more abundant in mPDT- than aPDT-treated cells and appeared earlier after mPDT (3 h) than after aPDT (3−12 h). Western Bloting results showed that the ratio of LC3B-II/β − actin at 3 h was higher (1.04 times) after mPDT than aPDT. Collectively, these datas indicated that ALA-mPDT was more effective than the same dose of ALA-aPDT at inducing SW837 CRC cell death via apoptosis and autophagy. Thus, mPDT may be a superior choice than aPDT for the treatment of human CRC.

Benzo[a]phenoselenazine-based NIR photosensitizer for tumor-targeting photodynamic therapy via lysosomal-disruption pathway

The ultimate goal of cancer therapy is to develop antitumor agents that will destroy selectively tumor cells while sparing the health cell of the patient. Herein, we reported a novel tumor-specific and lysosome dual-targeted NIR photosensitizer, Se-Biotin, by conjugating a biotin ligand into benzo[a]phenoselenazinium derivative dye for selective destruction of tumor cells. Attractively, co-culture model showed that Se-Biotin could selectively target to and retain in biotin receptor-overexpressed tumor cells, which as a result significantly minimized the side effects toward normal cells. As confirmed by the in vitro anticancer mechanism, after cellular internalization, upon irradiation, the effective1O2 generation (ΦΔ = 0.69)severely disrupted the lysosomalintegrity and subsequently led to apoptotic cell death. Benefiting from these merits, Se-Biotin successfully achieved a superior anticancer performance with the IC50 as low as 85 nM, only under a low light dose irradiation (12 J/cm2, 660 nm). Therefore, these result demonstrated that Se-Biotin will be a promising PDT agent for targeted cancer photodynamic therapy.

The potential use of oncolytic viruses in breast cancer: historical aspects and future prospects (literature review)

Viral oncolysis, an approach to cancer therapy that emerged in the XX century and based on the natural ability of viruses to kill (lyse) cells in which it multiplies, has been developed in recent years by identifying viruses or their engineering variants with selective tumor replication. Over the past decades, a number of specific interactions of oncolytic viruses (both RNA and IDNA-containing) with malignant tumor cells have been described, individual candidate viruses and the types of tumors that they lase have been detected. The therapeutic efficacy of oncolytic viruses is achieved through a combination of selective destruction of tumor cells through a direct cytotoxic effect and activation of antitumor immunity; In addition, oncolytic viruses can affect abberant signaling pathways followed by blockade of tumor cell apoptosis, which gives the virus more time to complete its life cycle. A number of oncolytic viruses have shown promising therapeutic efficacy in preclinical studies in breast cancer; thus, the herpes simplex virus has a high selectivity for replication in tumor cells, which contributes to the death and the formation of infiltration of CD8+ and CD4+ T cells around tumor islands. The ability of reoviruses to enhance the expression of PD-L1 protein in cells was found, and the measles virus armed with the BNiP3 proapoptosis gene is more active in the cell lines of triple negative breast cancer. Improved viruses, from the point of view of the effectiveness and selectivity of effects on the tumor, as well as optimized combinations with other "standard" types of systemic therapy, are very promising, especially in patients with developed drug resistance.

Anti-Cancer Effect of Tacrine-Coumarin Derivatives on Diverse Human and Mouse Cancer Cell Lines

Acridine derivatives were first used as antibacterial and antiparasitic agents, later as antimalarial and anti-HIV drugs, and now as potentially anti-cancer agents due to their high cytotoxic activity. Due to their serious adverse effects, new synthetic derivatives were introduced and tested based on modified naturally occurring substances, such as acridone derivatives, which also exhibit potential anti-tumor activity. Most of them are DNA-damaging substances, causing relatively strong and selective destruction of tumor cells. We have tested in vitro anti-proliferative effects of newly-synthesized tetrahydroacrid derivatives, namely tacrine-coumarin hybrid molecules, on various human and mouse cancer cell lines. Our results showed that tacrine-coumarin hybrids with seven, eight, and nine methylene groups in spacer reduce proliferation of cancer cells. A hybrid with nine methylene groups had the most significant anti-cancer effect.

Attaining threshold antibody cytotoxicity for selective tumor cell destruction: an opinion article.

We propose a novel immunotherapeutic paradigm that justifies application of several antibodies to various membrane-associated antigens to achieve a critical threshold density of immune complexes on the surface of cancer cells sufficient for triggering downstream cytolytic pathways. Indeed, some cancer-associated antigens (such as cancer/testis antigens) were found to be expressed on many cancer (but not normal) cells, with their baseline membrane expression levels being originally quite low for some of them, or even further down-regulated due to immune-driven cell selection. To achieve the mandatory threshold density of membrane-associated immune complexes on malignant cells, the concept stipulates combined application of antibodies specific for a cancer-associated antigen along with antibodies against an antigen expressed not only on tumor, but also on normal cells. In the proposed scenario it is of vital importance that the latter antibodies should be applied in suboptimal dosage to exclude the destruction of normal cells devoid of a cancer-associated antigen. Malignant cells often co-express antigens not present concurrently on normal cells at high levels. In such cases, suboptimal dosages of antibodies specific for those antigens could also be applied to achieve cumulative effect leading to selective destruction of tumour cells. Hence, the described immunotherapeutic technology could be used metaphorically speaking as a kind of ‘immunological knife’, which is capable of highly selective destruction of cancer cells without destroying normal cells.

Spatial and Temporal Confined Photothermolysis of Cancer Cells Mediated by Hollow Gold Nanospheres Targeted to Epidermal Growth Factor Receptors.

To date, a few studies have investigated the potential use of a short-pulsed laser in selective tumor cell destruction or its mechanism of cell killing. Computer simulation of the spatial and temporal profiles of temperature elevation after pulsed laser irradiation on an infinitesimal point source estimated that the temperature reached its highest point at ∼35 ns after a single 15 ns laser pulse. Moreover, temperature elevation was confined to a radius of sub-micrometer and returned to baseline within 100 ns. To investigate the effect of 15 ns laser pulses on A431 tumor cells, we conjugated hollow gold nanospheres (HAuNSs) to an antibody (C225) directed at the epithelial growth factor receptor. The resulting nanoparticles, C225-HAuNSs, bound to the cell membrane, internalized, and distributed throughout the cytoplasm, with some nanoparticles transported to the vicinity of the nuclear membrane. On using an optical microscope mounted to a tunable pulsed Ti:sapphire laser, rapid and extensive damage of live cancer cells was observed, whereas irradiation of A431 cells pretreated with nontargeted HAuNSs with a pulsed laser or pretreated with C225-HAuNSs with a continuous-wave laser-induced minimal cellular damage. Furthermore, after a single 15 ns laser pulse, C225-HAuNS-treated A431 cells cocultured with 3T3 fibroblasts showed signs of selective destruction. Thus, compared with a continuous-wave laser, shots of a short-pulsed laser were the most damaging to tumor cells that bound HAuNSs and generated the least heat to the surrounding environment. This mode of action by a short-pulsed laser on cancer cells (i.e., confined photothermolysis) may have potential applications in selective tumor cell destruction.

Development and evaluation of β-galactosidase-sensitive antibody-drug conjugates

The selective destruction of tumour cells while sparing healthy tissues is one of the main challenges in cancer therapy. Antibody-drug conjugates (ADCs) are arguably the most rapidly expanding class of targeted cancer therapies. Efficient drug conjugation and release technologies are essential for the development of these new therapeutic agents. In response to the ever-increasing demand for efficient drug release systems, we have developed a new class of β-galactosidase-cleavable linkers for ADCs. Within this framework, novel payloads comprising a galactoside linker, the monomethyl auristatin E (MMAE) and cysteine-reactive groups were synthesized, conjugated with trastuzumab and evaluated both in vitro and in vivo. The ADCs with galactoside linkers demonstrated superior therapeutic efficacy in mice compared to the marketed trastuzumab emtansine used for the treatment of breast cancer.

Development and Analysis of a Novel Parallel Manipulator Used in Four-Dimensional Radiotherapy

Radiotherapy (RT) enables a selective destruction of tumor cells, although the treatment area is limited to the irradiated volume. Any RT technique comes along with multiple sources of error, which can lead to a deviation of the dose that is applied to the patient. Phantoms—structures that replicate a human and include measurement technology to assess the applied dosage—are used to make such errors observable. Past RT-technologies assumed static tumors. Correspondingly, most existing phantoms comprise only static components. Nowadays, RT is at a transition stage toward techniques which explicitly account for physiological motion. These techniques require phantoms generating such motion. Consequentially, a demand for new kinds of manipulators, which operate with a RT-phantom, has come up and will further increase in the future. Key demands of such manipulators are among others, the generation of full rigid body motion, high acceleration, high stiffness, compactness, little weight, and easy portability. Another indispensable feature is the spatial separation of mechatronic components and phantom structure to ensure human equivalency of the latter. In this work, a new kind of parallel kinematic manipulator (PKM), which is tailored to the requirements of RT-phantom technology, is presented. The PKM consists of low cost standardized mechanical components and sets the target structures, which are located inside a human-equivalent area, into translational and rotational motion in three degrees-of-freedom (DOFs). Only a part of the end-effector is located within the human-equivalent area. All the remaining parts of the PKM are located outside that area. Two versions of the manipulator are presented in detail: their kinematics are derived and their kinetostatic properties are compared. This includes a workspace analysis and the analysis of the transmission behavior in general, meaning the influence of the most important design parameters on the performance. It can be shown that practical differences of both kinematics are negligible, while the modified version provides significant mechanical advantages. In conclusion, a first special purpose manipulator for application in the evolving field of RT-phantom technology is presented. The PKM, which employs a novel kinematic structure, provides higher suitability for its purpose than any other robotic system employed so far for the same purpose.

Arginine dependence of tumor cells: targeting a chink in cancer's armor.

Arginine, one among the 20 most common natural amino acids, has a pivotal role in cellular physiology as it is being involved in numerous cellular metabolic and signaling pathways. Dependence on arginine is diverse for both tumor and normal cells. Because of decreased expression of argininosuccinate synthetase and/or ornithine transcarbamoylase, several types of tumor are auxotrophic for arginine. Deprivation of arginine exploits a significant vulnerability of these tumor cells and leads to their rapid demise. Hence, enzyme-mediated arginine depletion is a potential strategy for the selective destruction of tumor cells. Arginase, arginine deiminase and arginine decarboxylase are potential enzymes that may be used for arginine deprivation therapy. These arginine catabolizing enzymes not only reduce tumor growth but also make them susceptible to concomitantly administered anti-cancer therapeutics. Most of these enzymes are currently under clinical investigations and if successful will potentially be advanced as anti-cancer modalities.

Study of Cold Atmospheric Plasma Jet at the End of Flexible Plastic Tube for Microbial Decontamination

Recently, cold atmospheric plasmas have demonstrated very promising antimicrobial activity in vitro and in vivo including selective destruction of tumor cells. However, the size and the rigidity of most plasma systems limit the clinical application for treatments in internal organs or regions with difficult access (e.g., mouth). Here, we report a device that allows ignition of cold He plasma jet at the tip of 1 m long, 3.5 mm diameter, flexible plastic tube. It is connected to a dielectric enclosure where dielectric barrier discharge (DBD) is generated by a low‐frequency AC power supply. A thin wire at floating potential put inside the plastic tube assists the formation of plasma jet at the downstream tube end. The flexible tube can be kept and manipulated by hand without electric shock and thus the plasma jet can be easily directed to a target. Variation of duty cycle of the applied voltage signal allows precise adjustment of the discharge power. The anti‐microbial efficiency of plasma jet system with flexible tube was tested against fungus Candida albicans seeded on agar.

Structural features in nano-ZnO-Folic acid conjugate system

Z oxide (ZnO) nanoparticles (grown in the template of folic acid) are biologically useful, luminescent material. It can be used for multifunctional purposes, such as biosensor, bioimaging, targeted drug delivery and as growth promoting medicine. Though, ZnO is categorized as: “generally recognized as safe” (GRAS) but ZnO nanoparticle system may be cytotoxic. ZnO nanosystem could be of important relevance in the context of nanomedicine, where targeted treatment of biological systems at molecular level is a necessity. ZnO quantum dots with their surface modification and bio-conjugation for selective destruction of tumor cells and their potential use for drug delivery applications is the cardinal issue of this presentation..

Catalytically active bovine serum amine oxidase bound to fluorescent and magnetically drivable nanoparticles

Novel superparamagnetic surface-active maghemite nanoparticles (SAMNs) characterized by a diameter of 10 ± 2 nm were modified with bovine serum amine oxidase, which used rhodamine B isothiocyanate (RITC) adduct as a fluorescent spacer-arm. A fluorescent and magnetically drivable adduct comprised of bovine serum copper-containing amine oxidase (SAMN–RITC–BSAO) that immobilized on the surface of specifically functionalized magnetic nanoparticles was developed. The multifunctional nanomaterial was characterized using transmission electron microscopy, infrared spectroscopy, mass spectrometry, and activity measurements. The results of this study demonstrated that bare magnetic nanoparticles form stable colloidal suspensions in aqueous solutions. The maximum binding capacity of bovine serum amine oxidase was approximately 6.4 mg g−1 nanoparticles. The immobilization procedure reduced the catalytic activity of the native enzyme to 30% ± 10% and the Michaelis constant was increased by a factor of 2. We suggest that the SAMN–RITC–BSAO complex, characterized by a specific activity of 0.81 IU g−1, could be used in the presence of polyamines to create a fluorescent magnetically drivable H2O2 and aldehydes-producing system. Selective tumor cell destruction is suggested as a potential future application of this system.

Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications

Importance of the field: Metal oxide nanoparticles, including zinc oxide, are versatile platforms for biomedical applications and therapeutic intervention. There is an urgent need to develop new classes of anticancer agents, and recent studies demonstrate that ZnO nanomaterials hold considerable promise.Areas covered in this review: This review analyzes the biomedical applications of metal oxide and ZnO nanomaterials under development at the experimental, preclinical and clinical levels. A discussion regarding the advantages, approaches and limitations surrounding the use of metal oxide nanoparticles for cancer applications and drug delivery is presented. The scope of this article is focused on ZnO, and other metal oxide nanomaterial systems, and their proposed mechanisms of cytotoxic action, as well as current approaches to improve their targeting and cytotoxicity against cancer cells.What the reader will gain: This review aims to give an overview of ZnO nanomaterials in biomedical applications.Take home message: Through a better understanding of the mechanisms of action and cellular consequences resulting from nanoparticles interactions with cells, the inherent toxicity and selectivity of ZnO nanoparticles against cancer may be improved further to make them attractive new anticancer agents.

Cell proliferation and cell cycle alterations in oesophageal p53‐mutated cancer cells treated with cisplatin in combination with photodynamic therapy

The major goal of anti-cancer therapies is selective destruction of tumour cells with minimum side effects on normal cells. Towards this aim, combination of different therapeutic modalities has been evaluated for improving control of neoplastic diseases and quality of life for the patient. Photodynamic therapy (PDT) is a procedure for treatment of various types of cancer, but its combination with other established treatments has not been evaluated in detail. We have used KYSE-510 cells from a human oesophageal carcinoma as an in vitro model to investigate whether cisplatin (CDDP) could be combined with PDT to increase cell death with respect to single treatments. p53-mutated KYSE-510 cells were treated with CDDP alone or in combination with PDT. Analyses of cell viability, cell cycle progression and apoptosis induction were carried out at specific times after treatments. Decrease in cell viability, cell cycle arrest at the G(2)/M- and S-phases boundary, and apoptosis induction were observed after single and combined treatments. Our results show that low CDDP doses (0.25-1 microm) induce cell mortality and cell cycle perturbation, which were more evident when given in combination with PDT, but in contrast to work of other authors no synergistic activity was found. Apoptosis occurred via intrinsic pathways in treated cells, although it did not represent the predominant mode of cell death.

New hopes from old drugs: revisiting DNA-binding small molecules as anticancer agents.

Most of the anticancer chemotherapeutic drugs that are broadly and successfully used today are DNA-damaging agents. Targeting of DNA has been proven to cause relatively potent and selective destruction of tumor cells. However, the clinical potential of DNA-damaging agents is limited by the adverse side effects and increased risk of secondary cancers that are consequences of the agents' genotoxicity. In this review, we present evidence that those agents capable of targeting DNA without inducing DNA damage would not be limited in these ways, and may be as potent as DNA-damaging agents in the killing of tumor cells. We use as an example literature data and our own research of the well-known antimalarial drug quinacrine, which binds to DNA without inducing DNA damage, yet modulates a number of cellular pathways that impact tumor cell survival.