scholarly journals Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

2012 ◽  
Vol 19 (3) ◽  
pp. 423-434 ◽  
Author(s):  
Kathrin Zitzmann ◽  
George Vlotides ◽  
Stephan Brand ◽  
Harald Lahm ◽  
Gerald Spöttl ◽  
...  
Keyword(s):  
Cell Viability ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Akt Inhibitor ◽  
Antitumor Effects ◽  
Akt Isoforms ◽  
Induced Apoptosis

The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system show aberrant Akt activity. Several inhibitors of the phosphoinositide 3-kinase (PI(3)K)–Akt–mTOR signaling pathway are currently being evaluated in clinical phase II and III studies for the treatment of NETs with promising results. However, the molecular mechanisms and particularly the role of different Akt isoforms in NET signaling are not fully understood. In this study, we examine the effect of Akt inhibition on NET cells of heterogeneous origin. We show that the Akt inhibitor perifosine effectively inhibits Akt phosphorylation and cell viability in human pancreatic (BON1), bronchus (NCI-H727), and midgut (GOT1) NET cells. Perifosine treatment suppressed the phosphorylation of Akt downstream targets such as GSK3α/β, MDM2, and p70S6K and induced apoptosis. To further investigate the role of individual Akt isoforms for NET cell function, we specifically blocked Akt1, Akt2, and Akt3 via siRNA transfection. In contrast to Akt2 knockdown, knockdown of Akt isoforms 1 and 3 decreased phosphorylation levels of GSK3α/β, MDM2, and p70S6K and suppressed NET cell viability and colony-forming capacity. The inhibitory effect of simultaneous downregulation of Akt1 and Akt3 on tumor cell viability was significantly stronger than that caused by downregulation of all Akt isoforms, suggesting a particular role for Akt1 and Akt3 in NET signaling. Akt3 siRNA-induced apoptosis while all three isoform-specific siRNAs impaired BON1 cell invasion. Together, our data demonstrate potent antitumor effects of the pan-Akt inhibitor perifosine on NET cells in vitro and suggest that selective targeting of Akt1 and/or Akt3 might improve the therapeutic potential of Akt inhibition in NET disease.

VDAC1 Mediated Anticancer Activity of Gallic Acid in Human Lung Adenocarcinoma A549 Cells

2018 ◽  
Vol 18 (2) ◽  
pp. 255-262 ◽  
Author(s):  
Aikebaier Maimaiti ◽  
Amier Aili ◽  
Hureshitanmu Kuerban ◽  
Xuejun Li
Keyword(s):  
Western Blot ◽  
Cell Viability ◽  
Gallic Acid ◽  
Molecular Mechanisms ◽  
A549 Cells ◽  
Dependent Manner ◽  
Lung Carcinoma Cells ◽  
Induced Apoptosis ◽  
The Impact

Aims: Gallic acid (GA) is generally distributed in a variety of plants and foods, and possesses cell growth-inhibiting activities in cancer cell lines. In the present study, the impact of GA on cell viability, apoptosis induction and possible molecular mechanisms in cultured A549 lung carcinoma cells was investigated. Methods: In vitro experiments showed that treating A549 cells with various concentrations of GA inhibited cell viability and induced apoptosis in a dose-dependent manner. In order to understand the mechanism by which GA inhibits cell viability, comparative proteomic analysis was applied. The changed proteins were identified by Western blot and siRNA methods. Results: Two-dimensional electrophoresis revealed changes that occurred to the cells when treated with or without GA. Four up-regulated protein spots were clearly identified as malate dehydrogenase (MDH), voltagedependent, anion-selective channel protein 1(VDAC1), calreticulin (CRT) and brain acid soluble protein 1(BASP1). VDAC1 in A549 cells was reconfirmed by western blot. Transfection with VDAC1 siRNA significantly increased cell viability after the treatment of GA. Further investigation showed that GA down regulated PI3K/Akt signaling pathways. These data strongly suggest that up-regulation of VDAC1 by GA may play an important role in GA-induced, inhibitory effects on A549 cell viability.

scholarly journals Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins

Blood ◽  
2009 ◽  
Vol 114 (9) ◽  
pp. 1987-1998 ◽  
Author(s):  
Tong-Young Lee ◽  
Stefan Muschal ◽  
Elke A. Pravda ◽  
Judah Folkman ◽  
Amir Abdollahi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Antiangiogenic Therapy ◽  
Krebs Cycle ◽  
In Vivo Studies ◽  
Antitumor Effects ◽  
Down Regulation ◽  
Proteolytic Fragment ◽  
Induced Apoptosis

Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow–derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin.

scholarly journals The Molecular Pathogenesis of Haemangioma

2021 ◽  
Author(s):  
◽  
Anasuya Vishvanath
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Primary Tumour ◽  
Treatment Options ◽  
Janus Kinase ◽  
Stem Cell Population ◽  
Induced Apoptosis

<p>Haemangioma is a primary tumour of the microvasculature characterised by active angiogenesis and endothelial cell (EC)  proliferation followed by slow regression or involution whereby the newly formed blood vessels are gradually replaced by fibrofatty tissue. These developmental changes have been arbitrarily divided into the proliferative, involuting and involuted phases. The cellular and molecular events that initiate and regulate the proliferation and spontaneous involution of haemangioma remain poorly understood. This study examined the expression of a number of genes known to be associated with angiogenesis. These include members of the signal transducers and activators of transcription (STAT) protein family of transcription factors, STAT-3 and STAT-1, and the endothelial receptor tyrosine kinases, VEGFR-1 and VEGFR-2. While STAT-3, STAT-1 and VEGFR-1 expression was detected in all phases of haemangioma, VEGFR-2 expression was found to be abundant only during the proliferative phase and decreased with ongoing involution. In this study the cellular structures that form capillary-like outgrowths in an in vitro haemangioma explant model were characterised as haemangioma-derived mesenchymal stem cells (HaemDMSCs) while the cells obtained directly from dissociated proliferative haemangioma tissue were defined as haemangioma-derived endothelial progenitor cells (HaemDEPCs). This investigation showed that although the vascular endothelial growth factor (VEGF), a key growth factor for ECs, was able to maintain HaemDEPCs morphology and immunophenotype for a limited period, these cells eventually differentiated into HaemDMSCs, which subsequently differentiated into adipocytes. Furthermore, while VEGF induced significant capillary-like sprouting from tissue explants, both capillary-like sprouting and HaemDMSCs proliferation was inhibited by the addition of AG490, a Janus kinase (JAK) inhibitor which has also been shown to inhibit the STAT protein pathway. These findings indicate that the development and differentiation of a progenitor cell and a stem cell population underlies the aethiopathogenesis of haemangioma and that VEGF and STAT signalling is involved in the programmed life-cycle of haemangioma. The in vitro explant model for haemangioma offers an opportunity to study and identify novel treatment options for haemangioma. Interferon-alpha (IFN ) has been used to treat steroid-resistant haemangioma but is associated with serious side-affects. The tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to specifically induce apoptosis of cancer cells while sparing normal cells. As IFN has previously been shown to sensitise cells to TRAIL-induced apoptosis, this study examined the efficacy of low dose IFN in combination with TRAIL in the in vitro explant model and also in the purified HaemDMSCs. Results showed that combining IFN with TRAIL led to synergistic inhibition of capillary-like outgrowth. These results indicate that IFN in combination with TRAIL serves as a potential treatment option for haemangioma. In contrast, HaemDMSCs were protected from TRAIL-induced killing. These cells were found to express high levels of the decoy receptors, osteoprotegerin (OPG) and decoy receptor 2 (DcR2). Increased OPG expression was also detected in the extracellular matrix and in the conditioned medium of HaemDMSCs. From these findings, we postulate that the increased level of extracellular OPG by HaemDMSCs is a stress response induced by their in vitro expansion and that secreted OPG functions as a protective shield preventing TRAIL action. The empirical and unsatisfactory nature of the current therapies for haemangioma underscores the importance of a scientific approach to this common tumour. A better understanding of the molecular mechanisms that govern haemangioma is of both clinical and biological interest as it may provide vital information with therapeutic potential for haemangioma and also for other angiogenesis-dependent conditions.</p>

scholarly journals Autophagy is activated to protect against podocyte injury in adriamycin-induced nephropathy

2017 ◽  
Vol 313 (1) ◽  
pp. F74-F84 ◽  
Author(s):  
Mixuan Yi ◽  
Lei Zhang ◽  
Yu Liu ◽  
Man J. Livingston ◽  
Jian-Kang Chen ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Glomerular Disease ◽  
Podocyte Injury ◽  
Knockout Mouse Model ◽  
Filtration Barrier ◽  
Induced Apoptosis ◽  
And Function

Podocytes are highly differentiated epithelial cells wrapping glomerular capillaries to form the filtration barrier in kidneys. As such, podocyte injury or dysfunction is a critical pathogenic event in glomerular disease. Autophagy plays an important role in the maintenance of the homeostasis and function of podocytes. However, it is less clear whether and how autophagy contributes to podocyte injury in glomerular disease. Here, we have examined the role of autophagy in adriamycin-induced nephropathy, a classic model of glomerular disease. We show that autophagy was induced by adriamycin in cultured podocytes in vitro and in podocytes in mice. In cultured podocytes, activation of autophagy with rapamycin led to the suppression of adriamycin-induced apoptosis, whereas inhibition of autophagy with chloroquine enhanced podocyte apoptosis during adriamycin treatment. To determine the role of autophagy in vivo, we established an inducible podocyte-specific autophagy-related gene 7 knockout mouse model (Podo-Atg7-KO). Compared with wild-type littermates, Podo-Atg7-KO mice showed higher levels of podocyte injury, glomerulopathy, and proteinuria during adriamycin treatment. Together, these observations support an important role of autophagy in protecting podocytes under the pathological conditions of glomerular disease, suggesting the therapeutic potential of autophagy induction.

scholarly journals Involvement of the Ca2+-responsive transactivator in high glucose-induced β-cell apoptosis

2012 ◽  
Vol 216 (2) ◽  
pp. 231-243 ◽  
Author(s):  
Xiuli Men ◽  
Liang Peng ◽  
Haiyan Wang ◽  
Wenjian Zhang ◽  
Shiqing Xu ◽  
...  
Keyword(s):  
High Glucose ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Induced Apoptosis ◽  
Sirna Knockdown

The calcium-regulated transcription coactivator, Ca2+-responsive transactivator (CREST) was expressed in pancreatic β-cells. Moreover, CREST expression became significantly increased in pancreatic islets isolated from hyperglycemic Goto–Kakizaki rats compared with normoglycemic Wistar controls. In addition, culture of β-cells in the presence of high glucose concentrations also increased CREST expression in vitro. To further investigate the role of this transactivator in the regulation of β-cell function, we established a stable β-cell line with inducible CREST expression. Hence, CREST overexpression mimicked the glucotoxic effects on insulin secretion and cell growth in β-cells. Moreover, high glucose-induced apoptosis was aggravated by upregulation of the transactivator but inhibited when CREST expression was partially silenced by siRNA technology. Further investigation found that upregulation of Bax and downregulation of Bcl2 was indeed induced by its expression, especially under high glucose conditions. In addition, as two causing factors leading to β-cell apoptosis under diabetic conditions, endoplasmic reticulum stress and high free fatty acid, mimicked the high glucose effects on CREST upregulation and generation of apoptosis in β-cells, and these effects were specifically offset by the siRNA knockdown of CREST. These results indicated that CREST is implicated in β-cell apoptosis induced by culture in high glucose and hence that CREST may become a potential pharmacological target for the prevention and treatment of type 2 diabetes mellitus.

scholarly journals Caspase-1 regulates Ang II-induced cardiomyocyte hypertrophy via up-regulation of IL-1β

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Yunlong Bai ◽  
Xi Sun ◽  
Qun Chu ◽  
Anqi Li ◽  
Ying Qin ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Compensatory Response ◽  
Caspase 1

Cardiac hypertrophy is a compensatory response to stress or stimuli, which results in arrhythmia and heart failure. Although multiple molecular mechanisms have been identified, cardiac hypertrophy is still difficult to treat. Pyroptosis is a caspase-1-dependent pro-inflammatory programmed cell death. Caspase-1 is involved in various types of diseases, including hepatic injury, cancers, and diabetes-related complications. However, the exact role of caspase-1 in cardiac hypertrophy is yet to be discovered. The present study aimed to explore the possible role of caspase-1 in pathogenesis of cardiac hypertrophy. We established cardiac hypertrophy models both in vivo and in vitro to detect the expression of caspase-1 and interleukin-1β (IL-1β). The results showed that caspase-1 and IL-1β expression levels were significantly up-regulated during cardiac hypertrophy. Subsequently, caspase-1 inhibitor was co-administered with angiotensin II (Ang II) in cardiomyocytes to observe whether it could attenuate cardiac hypertrophy. Results showed that caspase-1 attenuated the pro-hypertrophic effect of Ang II, which was related to the down-regulation of caspase-1 and IL-1β. In conclusion, our results provide a novel evidence that caspase-1 mediated pyroptosis is involved in cardiac hypertrophy, and the inhibition of caspase-1 will offer a therapeutic potential against cardiac hypertrophy.

scholarly journals The Role of TGF-β Signaling Pathways in Cancer and Its Potential as a Therapeutic Target

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Yun Yang ◽  
Wen-Long Ye ◽  
Ruo-Nan Zhang ◽  
Xiao-Shun He ◽  
Jing-Ru Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Immune Escape ◽  
Therapeutic Potential ◽  
Malignant Tumors ◽  
Transforming Growth Factor Β ◽  
Antitumor Effects ◽  
Downstream Signaling

The transforming growth factor-β (TGF-β) signaling pathway mediates various biological functions, and its dysregulation is closely related to the occurrence of malignant tumors. However, the role of TGF-β signaling in tumorigenesis and development is complex and contradictory. On the one hand, TGF-β signaling can exert antitumor effects by inhibiting proliferation or inducing apoptosis of cancer cells. On the other hand, TGF-β signaling may mediate oncogene effects by promoting metastasis, angiogenesis, and immune escape. This review summarizes the recent findings on molecular mechanisms of TGF-β signaling. Specifically, this review evaluates TGF-β′s therapeutic potential as a target by the following perspectives: ligands, receptors, and downstream signaling. We hope this review can trigger new ideas to improve the current clinical strategies to treat tumors related to the TGF-β signaling pathway.

scholarly journals miRNA-193a-3p Regulates the AKT2 Pathway to Inhibit the Growth and Promote the Apoptosis of Glioma Cells by Targeting ALKBH5

2021 ◽  
Vol 11 ◽  
Author(s):  
Yong Cui ◽  
Qi Wang ◽  
Jing Lin ◽  
Lei Zhang ◽  
Chi Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Luciferase Reporter ◽  
Physical Interaction ◽  
Antitumor Effects ◽  
Induced Apoptosis ◽  
U87 Cells

Emerging evidence indicates that microRNA (miR)-193a-3p is involved in the tumor progression of various cancers. However, the biological functions and precise molecular mechanisms of miR-193a-3p in gliomas have not been well documented. Accordingly, this study focused on the tumor suppressor role and molecular mechanisms of miR-193a-3p in glioma cells. miR-193a-3p expression was determined by qRT-PCR in glioma tissues and cell lines. U251 and U87 glioma cells were transfected with a miR-193a-3p mimic. The effects of miR-193a-3p on cell growth and apoptosis were investigated using MTT, colony-forming, and flow cytometry assays. Overexpression of miR-193a-3p in U87 cells also significantly suppressed tumorigenicity and induced apoptosis in the xenograft mouse model. Luciferase assays were conducted to determine if ALKBH5 is a direct target of miR-193a-3p in glioma cells. Immunoprecipitation was used to explore the interaction between ALKBH5 and RAC-serine/threonine-protein kinase 2 (AKT2) in glioma cells. miR-193a-3p was downregulated in glioma tissues and cell lines. miR-193a-3p treatment suppressed proliferation and promoted apoptosis in both U251 and U87 cells. Bioinformatics analysis and luciferase reporter assay identified a novel miR-193a-3p target, ALKBH5. Notably, the antitumor effect of miR-193a-3p transfection in glioma cells may be due to the miR-193a-3p–induced inhibition of AKT2 expression caused by the suppression of ALKBH5 expression. Furthermore, immunoprecipitation indicated that ALKBH5 physically interacted with AKT2 through an RNA-independent mechanism in glioma cells. miR-193a-3p directly targets ALKBH5 to inhibit the growth and promote the apoptosis of glioma cells by suppressing the AKT2 pathway both in vitro and in vivo, and the physical interaction between ALKBH5 and AKT2 is essential for suppressing cell apoptosis by upregulating miR-193a-3p in glioma cells. Our study revealed that the antitumor effects of miR-193a-3p on glioma cells is due to ALKBH5 mediation of the AKT2-induced intrinsic apoptosis signaling pathway.

scholarly journals The Molecular Pathogenesis of Haemangioma

2021 ◽  
Author(s):  
◽  
Anasuya Vishvanath
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Primary Tumour ◽  
Treatment Options ◽  
Janus Kinase ◽  
Stem Cell Population ◽  
Induced Apoptosis

<p>Haemangioma is a primary tumour of the microvasculature characterised by active angiogenesis and endothelial cell (EC)  proliferation followed by slow regression or involution whereby the newly formed blood vessels are gradually replaced by fibrofatty tissue. These developmental changes have been arbitrarily divided into the proliferative, involuting and involuted phases. The cellular and molecular events that initiate and regulate the proliferation and spontaneous involution of haemangioma remain poorly understood. This study examined the expression of a number of genes known to be associated with angiogenesis. These include members of the signal transducers and activators of transcription (STAT) protein family of transcription factors, STAT-3 and STAT-1, and the endothelial receptor tyrosine kinases, VEGFR-1 and VEGFR-2. While STAT-3, STAT-1 and VEGFR-1 expression was detected in all phases of haemangioma, VEGFR-2 expression was found to be abundant only during the proliferative phase and decreased with ongoing involution. In this study the cellular structures that form capillary-like outgrowths in an in vitro haemangioma explant model were characterised as haemangioma-derived mesenchymal stem cells (HaemDMSCs) while the cells obtained directly from dissociated proliferative haemangioma tissue were defined as haemangioma-derived endothelial progenitor cells (HaemDEPCs). This investigation showed that although the vascular endothelial growth factor (VEGF), a key growth factor for ECs, was able to maintain HaemDEPCs morphology and immunophenotype for a limited period, these cells eventually differentiated into HaemDMSCs, which subsequently differentiated into adipocytes. Furthermore, while VEGF induced significant capillary-like sprouting from tissue explants, both capillary-like sprouting and HaemDMSCs proliferation was inhibited by the addition of AG490, a Janus kinase (JAK) inhibitor which has also been shown to inhibit the STAT protein pathway. These findings indicate that the development and differentiation of a progenitor cell and a stem cell population underlies the aethiopathogenesis of haemangioma and that VEGF and STAT signalling is involved in the programmed life-cycle of haemangioma. The in vitro explant model for haemangioma offers an opportunity to study and identify novel treatment options for haemangioma. Interferon-alpha (IFN ) has been used to treat steroid-resistant haemangioma but is associated with serious side-affects. The tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to specifically induce apoptosis of cancer cells while sparing normal cells. As IFN has previously been shown to sensitise cells to TRAIL-induced apoptosis, this study examined the efficacy of low dose IFN in combination with TRAIL in the in vitro explant model and also in the purified HaemDMSCs. Results showed that combining IFN with TRAIL led to synergistic inhibition of capillary-like outgrowth. These results indicate that IFN in combination with TRAIL serves as a potential treatment option for haemangioma. In contrast, HaemDMSCs were protected from TRAIL-induced killing. These cells were found to express high levels of the decoy receptors, osteoprotegerin (OPG) and decoy receptor 2 (DcR2). Increased OPG expression was also detected in the extracellular matrix and in the conditioned medium of HaemDMSCs. From these findings, we postulate that the increased level of extracellular OPG by HaemDMSCs is a stress response induced by their in vitro expansion and that secreted OPG functions as a protective shield preventing TRAIL action. The empirical and unsatisfactory nature of the current therapies for haemangioma underscores the importance of a scientific approach to this common tumour. A better understanding of the molecular mechanisms that govern haemangioma is of both clinical and biological interest as it may provide vital information with therapeutic potential for haemangioma and also for other angiogenesis-dependent conditions.</p>

Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

2019 ◽  
Vol 14 (3) ◽  
pp. 219-225 ◽  
Author(s):  
Cong Tang ◽  
Guodong Zhu
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transmembrane Receptors ◽  
Biological Responses ◽  
Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

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