Fc-Binding Antibody-Recruiting Molecules for Cancer Therapy: Exploiting Endogenous IgG Without antigen–Fab Interactions

2019 ◽  
Author(s):  
Koichi Sasaki ◽  
Minori Harada ◽  
Yoshiki Miyashita ◽  
Hiroshi Tagawa ◽  
Akihiro Kishimura ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cancer Cells ◽  
Ternary Complex ◽  
Human Cancer ◽  
Folate Receptor ◽  
Xenograft Model ◽  
Effector Functions ◽  
Mouse Xenograft Model ◽  
Clinical Benefits ◽  
Binding Antibody

<div><div><div><p>Small molecules emulating the effector functions of antibodies have potential clinical benefits because of their low immunogenicity. Antibody-recruiting molecules (ARMs) are bispecific molecules designed to redirect endogenous antibodies to targets. However, endogenous antibodies show intra/inter-patient differences regarding their concentrations and affinities, limiting the potential of ARMs. We sought to address this issue using a Fc-binding peptide instead of an antigen for antibody redirection. Fc-binding ARM (Fc-ARM) targeting folate receptor-α (FR-α) expressed on cancer cells, formed a ternary complex of Fc-ARM, FR-α, and antibody on cancer cells. The ability of this ternary complex to activate natural killer cells was positively correlated with its Fc affinity, and did not require the Fab region. Fc-ARM hitchhiked on pooled human IgG to enhance its blood retention, and suppressed tumor growth in a mouse xenograft model of human cancer. Thus, Fc-ARM has the potential to be employed as a less immunogenic alternative to therapeutic antibodies.</p></div></div></div>

scholarly journals Fc-Binding Antibody-Recruiting Molecules for Cancer Therapy: Exploiting Endogenous IgG Without antigen–Fab Interactions

2019 ◽  
Author(s):  
Koichi Sasaki ◽  
Minori Harada ◽  
Yoshiki Miyashita ◽  
Hiroshi Tagawa ◽  
Akihiro Kishimura ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cancer Cells ◽  
Ternary Complex ◽  
Human Cancer ◽  
Folate Receptor ◽  
Xenograft Model ◽  
Effector Functions ◽  
Mouse Xenograft Model ◽  
Clinical Benefits ◽  
Binding Antibody

<div><div><div><p>Small molecules emulating the effector functions of antibodies have potential clinical benefits because of their low immunogenicity. Antibody-recruiting molecules (ARMs) are bispecific molecules designed to redirect endogenous antibodies to targets. However, endogenous antibodies show intra/inter-patient differences regarding their concentrations and affinities, limiting the potential of ARMs. We sought to address this issue using a Fc-binding peptide instead of an antigen for antibody redirection. Fc-binding ARM (Fc-ARM) targeting folate receptor-α (FR-α) expressed on cancer cells, formed a ternary complex of Fc-ARM, FR-α, and antibody on cancer cells. The ability of this ternary complex to activate natural killer cells was positively correlated with its Fc affinity, and did not require the Fab region. Fc-ARM hitchhiked on pooled human IgG to enhance its blood retention, and suppressed tumor growth in a mouse xenograft model of human cancer. Thus, Fc-ARM has the potential to be employed as a less immunogenic alternative to therapeutic antibodies.</p></div></div></div>

scholarly journals Arsenic nano complex induced degradation of YAP sensitized ESCC cancer cells to radiation and chemotherapy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wei Zhou ◽  
Meiyue Liu ◽  
Xia Li ◽  
Peng Zhang ◽  
Jiong Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Radiation Therapy ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Xenograft Model ◽  
Ros Production ◽  
Protective Effects ◽  
Migration Ability ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Abstract Background Increased reactive oxygen species (ROS) production by arsenic treatment in solid tumors showed to be effective to sensitize cancer cells to chemotherapies. Arsenic nano compounds are known to increase the ROS production in solid tumors. Methods In this study we developed arsenic–ferrosoferric oxide conjugated Nano Complex (As2S2–Fe3O4, AFCNC) to further promote the ROS induction ability of arsenic reagent in solid tumors. We screen for the molecular pathways that are affect by arsenic treatment in ESCC cancer cells. And explored the underlying molecular mechanism for the arsenic mediated degradations of the key transcription factor we identified in the gene microarray screen. Mouse xenograft model were used to further verify the synthetic effects of AFCNC with chemo and radiation therapies, and the molecular target of arsenic treatment is verified with IHC analysis. Results With gene expression microarray analysis we found Hippo signaling pathway is specifically affected by arsenic treatment, and induced ubiquitination mediated degradation of YAP in KYSE-450 esophageal squamous cell carcinoma (ESCC) cells. Mechanistically we proved PML physically interacted with YAP, and arsenic induced degradation PML mediated the degradation of YAP in ESCC cells. As a cancer stem cell related transcription factor, YAP 5SA over expressions in cancer cells are correlated with resistance to chemo and radiation therapies. We found AFCNC treatment inhibited the increased invasion and migration ability of YAP 5SA overexpressing KYSE-450 cells. AFCNC treatment also effectively reversed protective effects of YAP 5SA overexpression against cisplatin induced apoptosis in KYSE-450 cells. Lastly, with ESCC mouse xenograft model we found AFCNC combined with cisplatin treatment or radiation therapy significantly reduced the tumor volumes in vivo in the xenograft ESCC tumors. Conclusions Together, these findings suggested besides ROS, YAP is a potential target for arsenic based therapy in ESCC, which should play an important role in the synthetic effects of arsenic nano complex with chemo and radiation therapy.

scholarly journals An Anti-PSMA Immunotoxin Reduces Mcl-1 and Bcl2A1 and Specifically Induces in Combination with the BAD-Like BH3 Mimetic ABT-737 Apoptosis in Prostate Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1648
Author(s):  
Anie P. Masilamani ◽  
Viviane Dettmer-Monaco ◽  
Gianni Monaco ◽  
Toni Cathomen ◽  
Irina Kuckuck ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Target Cells ◽  
Prostate Cancer Cells ◽  
Mouse Xenograft Model ◽  
Synergistic Cytotoxicity ◽  
3D Spheroids

Background: Upregulation of anti-apoptotic Bcl-2 proteins in advanced prostate cancer leads to therapeutic resistance by prevention of cell death. New therapeutic approaches aim to target the Bcl-2 proteins for the restoration of apoptosis. Methods: The immunotoxin hD7-1(VL-VH)-PE40 specifically binds to the prostate specific membrane antigen (PSMA) on prostate cancer cells and inhibits protein biosynthesis. It was tested with respect to its effects on the expression of anti-apoptotic Bcl-2 proteins. Combination with the BAD-like mimetic ABT-737 was examined on prostate cancer cells and 3D spheroids and in view of tumor growth and survival in the prostate cancer SCID mouse xenograft model. Results: The immunotoxin led to a specific inhibition of Mcl-1 and Bcl2A1 expression in PSMA expressing target cells. Its combination with ABT-737, which inhibits Bcl-2, Bcl-xl, and Bcl-w, led to an induction of the intrinsic apoptotic pathway and to a synergistic cytotoxicity in prostate cancer cells and 3D spheroids. Furthermore, combination therapy led to a significantly prolonged survival of mice bearing prostate cancer xenografts based on an inhibition of tumor growth. Conclusion: The combination therapy of anti-PSMA immunotoxin plus ABT-737 represents the first tumor-specific therapeutic approach on the level of Bcl-2 proteins for the induction of apoptosis in prostate cancer.

scholarly journals Spironolactone, a Classic Potassium-Sparing Diuretic, Reduces Survivin Expression and Chemosensitizes Cancer Cells to Non-DNA-Damaging Anticancer Drugs

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1550 ◽  
Author(s):  
Tomomi Sanomachi ◽  
Shuhei Suzuki ◽  
Keita Togashi ◽  
Asuka Sugai ◽  
Shizuka Seino ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Kinase Inhibitors ◽  
Xenograft Model ◽  
Growth Factor Receptor ◽  
Survivin Expression ◽  
Mouse Xenograft Model ◽  
Anti Cancer ◽  
Underlying Mechanisms

Spironolactone, a classical diuretic drug, is used to treat tumor-associated complications in cancer patients. Spironolactone was recently reported to exert anti-cancer effects by suppressing DNA damage repair. However, it currently remains unclear whether spironolactone exerts combinational effects with non-DNA-damaging anti-cancer drugs, such as gemcitabine and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Using the cancer cells of lung cancer, pancreatic cancer, and glioblastoma, the combinational effects of spironolactone with gemcitabine and osimertinib, a third-generation EGFR-TKI, were examined in vitro with cell viability assays. To elucidate the underlying mechanisms, we investigated alterations induced in survivin, an anti-apoptotic protein, by spironolactone as well as the chemosensitization effects of the suppression of survivin by YM155, an inhibitor of survivin, and siRNA. We also examined the combinational effects in a mouse xenograft model. The results obtained revealed that spironolactone augmented cell death and the suppression of cell growth by gemcitabine and osimertinib. Spironolactone also reduced the expression of survivin in these cells, and the pharmacological and genetic suppression of survivin sensitized cells to gemcitabine and osimertinib. This combination also significantly suppressed tumor growth without apparent adverse effects in vivo. In conclusion, spironolactone is a safe candidate drug that exerts anti-cancer effects in combination with non-DNA-damaging drugs, such as gemcitabine and osimertinib, most likely through the suppression of survivin.

scholarly journals FAK-Copy-Gain Is a Predictive Marker for Sensitivity to FAK Inhibition in Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1288 ◽  
Author(s):  
Young-Ho Kim ◽  
Hyun-Kyoung Kim ◽  
Hee Yeon Kim ◽  
HyeRan Gawk ◽  
Seung-Hyun Bae ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Candidate Genes ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Xenograft Model ◽  
Predictive Marker ◽  
Marker Genes ◽  
Mouse Xenograft Model ◽  
Apoptotic Effect

Background: Cancers with copy-gain drug-target genes are excellent candidates for targeted therapy. In order to search for new predictive marker genes, we investigated the correlation between sensitivity to targeted drugs and the copy gain of candidate target genes in NCI-60 cells. Methods: For eight candidate genes showing copy gains in NCI-60 cells identified in our previous study, sensitivity to corresponding target drugs was tested on cells showing copy gains of the candidate genes. Results: Breast cancer cells with Focal Adhesion Kinase (FAK)-copy-gain showed a significantly higher sensitivity to the target inhibitor, FAK inhibitor 14 (F14). In addition, treatment of F14 or FAK-knockdown showed a specific apoptotic effect only in breast cancer cells showing FAK-copy-gain. Expression-profiling analyses on inducible FAK shRNA-transfected cells showed that FAK/AKT signaling might be important to the apoptotic effect by target inhibition. An animal experiment employing a mouse xenograft model also showed a significant growth-inhibitory effect of F14 on breast cancer cells showing FAK-copy-gain, but not on those without FAK-copy-gain. Conclusion: FAK-copy-gain may be a predictive marker for FAK inhibition therapy in breast cancer.

scholarly journals Two-stage nanoparticle delivery of piperlongumine and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) anti-cancer therapy

TECHNOLOGY ◽  
2016 ◽  
Vol 04 (01) ◽  
pp. 60-69 ◽  
Author(s):  
Charles C. Sharkey ◽  
Jiahe Li ◽  
Sweta Roy ◽  
Qianhui Wu ◽  
Michael R. King
Keyword(s):  
Cancer Cells ◽  
Survival Rates ◽  
Xenograft Model ◽  
Plga Nanoparticles ◽  
Mouse Xenograft Model ◽  
Anti Cancer ◽  
In Vivo Testing ◽  
Hct116 Cells

This study outlines a drug delivery mechanism that utilizes two independent vehicles, allowing for delivery of chemically and physically distinct agents. The mechanism was utilized to deliver a new anti-cancer combination therapy consisting of piperlongumine (PL) and TRAIL to treat PC3 prostate cancer and HCT116 colon cancer cells. PL, a small-molecule hydrophobic drug, was encapsulated in poly (lactic-co-glycolic acid) (PLGA) nanoparticles. TRAIL was chemically conjugated to the surface of liposomes. PL was first administered to sensitize cancer cells to the effects of TRAIL. PC3 and HCT116 cells had lower survival rates in vitro after receiving the dual nanoparticle therapy compared to each agent individually. In vivo testing involved a subcutaneous mouse xenograft model using NOD-SCID gamma mice and HCT116 cells. Two treatment cycles were administered over 48 hours. Higher apoptotic rates were observed for HCT116 tumor cells that received the dual nanoparticle therapy compared to individual stages of the nanoparticle therapy alone.

scholarly journals ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Wei-Ta Chen ◽  
Nancy D Ebelt ◽  
Travis H Stracker ◽  
Blerta Xhemalce ◽  
Carla L Van Den Berg ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Migration ◽  
Cancer Cells ◽  
Metastatic Cancer ◽  
Xenograft Model ◽  
Metastatic Potential ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Mouse Xenograft Model ◽  
Cancer Suppression

Ataxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression. Here we report a cancer-promoting role for ATM. ATM depletion in metastatic cancer cells reduced cell migration and invasion. Transcription analyses identified a gene network, including the chemokine IL-8, regulated by ATM. IL-8 expression required ATM and was regulated by oxidative stress. IL-8 was validated as an ATM target by its ability to rescue cell migration and invasion defects in ATM-depleted cells. Finally, ATM-depletion in human breast cancer cells reduced lung tumors in a mouse xenograft model and clinical data validated IL-8 in lung metastasis. These findings provide insights into how ATM activation by oxidative stress regulates IL-8 to sustain cell migration and invasion in cancer cells to promote metastatic potential. Thus, in addition to well-established roles in tumor suppression, these findings identify a role for ATM in tumor progression.

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