bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Fig from S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells
Authors: Wang Dongmei , Zhao Zhenwen , Caperell-Grant Andrea , Yang Gong , Mok Samuel C. , Liu Jinsong , Bigsby Robert M. , Xu Yan
Published: April 2023

Supplementary Fig from S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells
Supplementary Data from S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells
Authors: Wang Dongmei , Zhao Zhenwen , Caperell-Grant Andrea , Yang Gong , Mok Samuel C. , Liu Jinsong , Bigsby Robert M. , Xu Yan
Published: April 2023

Supplementary Data from S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells
Supplementary Table S1 from Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3′-untranslated region
Authors: Kandasamy Karthikeyan , Kraft Andrew S.
Published: April 2023

Supplementary Table S1 from Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3′-untranslated region
Supplementary Table S1 from Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth
Authors: Takahashi Tetsuyuki , Uehara Hisanori , Bando Yoshimi , Izumi Keisuke
Published: April 2023

Supplementary Table S1 from Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth
Supplementary Fig. S1 from Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth
Authors: Takahashi Tetsuyuki , Uehara Hisanori , Bando Yoshimi , Izumi Keisuke
Published: April 2023

Supplementary Fig. S1 from Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth
Supplementary Fig. S1 from Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3′-untranslated region
Authors: Kandasamy Karthikeyan , Kraft Andrew S.
Published: April 2023

Supplementary Fig. S1 from Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3′-untranslated region
Supplementary Table 1 from ALK1-Fc Inhibits Multiple Mediators of Angiogenesis and Suppresses Tumor Growth
Authors: Mitchell Dianne , Pobre Eileen G. , Mulivor Aaron W. , Grinberg Asya V. , Castonguay Roselyne , Monnell Travis E. , Solban Nicolas , Ucran Jeffrey A. , Pearsall R. Scott , Underwood Kathryn W. , Seehra Jasbir , Kumar Ravindra
Published: April 2023

Supplementary Table 1 from ALK1-Fc Inhibits Multiple Mediators of Angiogenesis and Suppresses Tumor Growth
Supplementary Table S4 from Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity
Authors: Kumar Rakesh , Knick Victoria B. , Rudolph Sharon K. , Johnson Jennifer H. , Crosby Renae M. , Crouthamel Ming-Chih , Hopper Teresa M. , Miller Charles G. , Harrington Laura E. , Onori James A. , Mullin Robert J. , Gilmer Tona M. , Truesdale Anne T. , Epperly Andrea H. , Boloor Amogh , Stafford Jeffrey A. , Luttrell Deirdre K. , Cheung Mui
Published: April 2023

Supplementary Table S4 from Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity
Supplementary Table S1 from Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity
Authors: Kumar Rakesh , Knick Victoria B. , Rudolph Sharon K. , Johnson Jennifer H. , Crosby Renae M. , Crouthamel Ming-Chih , Hopper Teresa M. , Miller Charles G. , Harrington Laura E. , Onori James A. , Mullin Robert J. , Gilmer Tona M. , Truesdale Anne T. , Epperly Andrea H. , Boloor Amogh , Stafford Jeffrey A. , Luttrell Deirdre K. , Cheung Mui
Published: April 2023

Supplementary Table S1 from Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity
Supplementary Fig. S1 from The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway
Authors: Elrod Heath A. , Lin Yi-Dan , Yue Ping , Wang Xuerong , Lonial Sagar , Khuri Fadlo R. , Sun Shi-Yong
Published: April 2023

Supplementary Fig. S1 from The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway
Supplementary Table S1 from Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma
Authors: Wong W. Wei-Lynn , Clendening James W. , Martirosyan Anna , Boutros Paul C. , Bros Christina , Khosravi Fereshteh , Jurisica Igor , Stewart A. Keith , Bergsagel P. Leif , Penn Linda Z.
Published: April 2023

PDF file - 84 KB, Differentially expressed cells in genes upon exposure to 20 muM lovastatin in resistant MM cell lines (LP1).
Supplements 1-5 from Gene expression profiling of whole-blood samples from women exposed to hormone replacement therapy
Authors: Dumeaux Vanessa , Johansen Jostein , Børresen-Dale Anne-Lise , Lund Eiliv
Published: April 2023

1 Figure and 4 Tables
Adobe PDF - MCT-06-0767--Suppl_Materials.pdf from 2-Methoxy antimycin reveals a unique mechanism for Bcl-xL inhibition
Authors: Schwartz Pamela S. , Manion Michael K. , Emerson Christine B. , Fry John S. , Schulz Craig M. , Sweet Ian R. , Hockenbery David M.
Published: April 2023

Adobe PDF - MCT-06-0767--Suppl_Materials.pdf from 2-Methoxy antimycin reveals a unique mechanism for Bcl-xL inhibition
Supplementary Fig. S1 from Role of placenta growth factor in malignancy and evidence that an antagonistic PlGF/Flt-1 peptide inhibits the growth and metastasis of human breast cancer xenografts
Authors: Taylor Alice P. , Goldenberg David M.
Published: April 2023

Supplementary Fig. S1 from Role of placenta growth factor in malignancy and evidence that an antagonistic PlGF/Flt-1 peptide inhibits the growth and metastasis of human breast cancer xenografts
Supplementary Table S2 from Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway
Authors: Ke Ning , Sundaram Roshni , Liu Guohong , Chionis John , Fan Wufang , Rogers Cheryl , Awad Tarif , Grifman Mirta , Yu Dehua , Wong-Staal Flossie , Li Qi-Xiang
Published: April 2023

Supplementary Table S2 from Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway
Supplementary Table S1 from Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway
Authors: Ke Ning , Sundaram Roshni , Liu Guohong , Chionis John , Fan Wufang , Rogers Cheryl , Awad Tarif , Grifman Mirta , Yu Dehua , Wong-Staal Flossie , Li Qi-Xiang
Published: April 2023

Supplementary Table S1 from Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway
Supplementary Fig. S2 from Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway
Authors: Ke Ning , Sundaram Roshni , Liu Guohong , Chionis John , Fan Wufang , Rogers Cheryl , Awad Tarif , Grifman Mirta , Yu Dehua , Wong-Staal Flossie , Li Qi-Xiang
Published: April 2023

Supplementary Fig. S2 from Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway
Supplementary Data from Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway
Authors: Ke Ning , Sundaram Roshni , Liu Guohong , Chionis John , Fan Wufang , Rogers Cheryl , Awad Tarif , Grifman Mirta , Yu Dehua , Wong-Staal Flossie , Li Qi-Xiang
Published: April 2023

Supplementary Data from Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway
Supplementary Fig. S2 from Suppression of cervical carcinoma cell growth by intracytoplasmic codelivery of anti-oncoprotein E6 antibody and small interfering RNA
Authors: Courtête Jérôme , Sibler Annie-Paule , Zeder-Lutz Gabrielle , Dalkara Deniz , Oulad-Abdelghani Mustapha , Zuber Guy , Weiss Etienne
Published: April 2023

Supplementary Fig. S2 from Suppression of cervical carcinoma cell growth by intracytoplasmic codelivery of anti-oncoprotein E6 antibody and small interfering RNA
Supplementary Fig. S1 from Suppression of cervical carcinoma cell growth by intracytoplasmic codelivery of anti-oncoprotein E6 antibody and small interfering RNA
Authors: Courtête Jérôme , Sibler Annie-Paule , Zeder-Lutz Gabrielle , Dalkara Deniz , Oulad-Abdelghani Mustapha , Zuber Guy , Weiss Etienne
Published: April 2023

Supplementary Fig. S1 from Suppression of cervical carcinoma cell growth by intracytoplasmic codelivery of anti-oncoprotein E6 antibody and small interfering RNA
Supplementary Table S1 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Authors: Weisberg Ellen , Kung Andrew L. , Wright Renee D. , Moreno Daisy , Catley Laurie , Ray Arghya , Zawel Leigh , Tran Mary , Cools Jan , Gilliland Gary , Mitsiades Constantine , McMillin Douglas W. , Jiang Jingrui , Hall-Meyers Elizabeth , Griffin James D.
Published: April 2023

Supplementary Table S1 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Supplementary Figure Legends from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Authors: Weisberg Ellen , Kung Andrew L. , Wright Renee D. , Moreno Daisy , Catley Laurie , Ray Arghya , Zawel Leigh , Tran Mary , Cools Jan , Gilliland Gary , Mitsiades Constantine , McMillin Douglas W. , Jiang Jingrui , Hall-Meyers Elizabeth , Griffin James D.
Published: April 2023

Supplementary Figure Legends from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Supplementary Fig. S8 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Authors: Weisberg Ellen , Kung Andrew L. , Wright Renee D. , Moreno Daisy , Catley Laurie , Ray Arghya , Zawel Leigh , Tran Mary , Cools Jan , Gilliland Gary , Mitsiades Constantine , McMillin Douglas W. , Jiang Jingrui , Hall-Meyers Elizabeth , Griffin James D.
Published: April 2023

Supplementary Fig. S8 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Supplementary Fig. S6 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Authors: Weisberg Ellen , Kung Andrew L. , Wright Renee D. , Moreno Daisy , Catley Laurie , Ray Arghya , Zawel Leigh , Tran Mary , Cools Jan , Gilliland Gary , Mitsiades Constantine , McMillin Douglas W. , Jiang Jingrui , Hall-Meyers Elizabeth , Griffin James D.
Published: April 2023

Supplementary Fig. S6 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Supplementary Fig. S5 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Authors: Weisberg Ellen , Kung Andrew L. , Wright Renee D. , Moreno Daisy , Catley Laurie , Ray Arghya , Zawel Leigh , Tran Mary , Cools Jan , Gilliland Gary , Mitsiades Constantine , McMillin Douglas W. , Jiang Jingrui , Hall-Meyers Elizabeth , Griffin James D.
Published: April 2023

Supplementary Fig. S5 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Supplementary Fig. S4 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Authors: Weisberg Ellen , Kung Andrew L. , Wright Renee D. , Moreno Daisy , Catley Laurie , Ray Arghya , Zawel Leigh , Tran Mary , Cools Jan , Gilliland Gary , Mitsiades Constantine , McMillin Douglas W. , Jiang Jingrui , Hall-Meyers Elizabeth , Griffin James D.
Published: April 2023

Supplementary Fig. S4 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Supplementary Fig. S1 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Authors: Weisberg Ellen , Kung Andrew L. , Wright Renee D. , Moreno Daisy , Catley Laurie , Ray Arghya , Zawel Leigh , Tran Mary , Cools Jan , Gilliland Gary , Mitsiades Constantine , McMillin Douglas W. , Jiang Jingrui , Hall-Meyers Elizabeth , Griffin James D.
Published: April 2023

Supplementary Fig. S1 from Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Supplementary Materials 1 & 2 from Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors
Authors: Helguera Gustavo , Rodríguez José A. , Penichet Manuel L.
Published: April 2023

Supplementary Materials 1 & 2 from Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors
Data from Curcumin suppresses constitutive activation of nuclear factor-κB and requires functional Bax to induce apoptosis in Burkitt's lymphoma cell lines
Authors: Hussain Azhar R. , Ahmed Maqbool , Al-Jomah Naif A. , Khan Asma S. , Manogaran Pulicat , Sultana Mehar , Abubaker Jehad , Platanias Leonidas C. , Al-Kuraya Khawla S. , Uddin Shahab
Published: April 2023

Abstract
We provide evidence that curcumin, a natural compound isolated from rhizomes of plant Curcuma longa, induces apoptosis in several Burkitt's lymphoma cell lines expressing Bax protein (AS283A, KK124, and Pa682PB), whereas it has no effects in cell lines with no Bax expression (BML895 and CA46). Our data show that curcumin treatment results in down-regulation of constitutive activation of nuclear factor-κB (NF-κB) via generation of reactive oxygen species where it causes conformational changes in Bax protein leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. This leads to activation of caspase-9, caspase-3, and poly(ADP)-ribose polymerase cleavage leading to caspase-dependent apoptosis. In addition, curcumin treatment of Burkitt's lymphoma cell lines also causes up-regulation of DR5; however, this up-regulation does not result in apoptosis. Importantly, cotreatment with curcumin and TRAIL induces apoptosis in Bax-deficient cell lines. Taken together, our findings suggest that curcumin is able to induce apoptosis in Bax-positive cell lines, whereas combinations with TRAIL result in apoptosis in Bax-negative cell lines. These findings also raise the possibility that incorporation of curcumin in treatment regimens may provide a novel approach for the treatment of Burkitt's lymphomas and provide the molecular basis for such future translational efforts. [Mol Cancer Ther 2008;7(10):3318–29]
Data from Optimization of antibody binding to FcγRIIa enhances macrophage phagocytosis of tumor cells
Authors: Richards John O. , Karki Sher , Lazar Greg A. , Chen Hsing , Dang Wei , Desjarlais John R.
Published: April 2023

Abstract
The contribution of Fc-mediated effector functions to the therapeutic efficacy of some monoclonal antibodies has motivated efforts to enhance interactions with Fcγ receptors (FcγR). Although an early goal has been enhanced FcγRIIIa binding and natural killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), other relevant cell types such as macrophages are dependent on additional activating receptors such as FcγRIIa. Here, we describe a set of engineered Fc variants with diverse FcγR affinities, including a novel substitution G236A that provides selectively enhanced binding to FcγRIIa relative to FcγRIIb. Variants containing this substitution have up to 70-fold greater FcγRIIa affinity and 15-fold improvement in FcγRIIa/FcγRIIb ratio and mediate enhanced phagocytosis of antibody-coated target cells by macrophages. Specific double and triple combination variants with this substitution are simultaneously capable of exhibiting high NK-mediated ADCC and high macrophage phagocytosis. In addition, we have used this unique set of variants to quantitatively probe the relative contributions of individual FcγR to effector functions mediated by NK cells and macrophages. These experiments show that FcγRIIa plays the most influential role for macrophages and, surprisingly, that the inhibitory receptor FcγRIIb has little effect on effector function. The enhancements in phagocytosis described here provide the potential to improve the performance of therapeutic antibodies targeting cancers. [Mol Cancer Ther 2008;7(8):2517–27]
Data from αvβ3 Integrin-dependent antiangiogenic activity of resveratrol stereoisomers
Authors: Belleri Mirella , Ribatti Domenico , Savio Monica , Stivala Lucia Anna , Forti Luca , Tanghetti Elena , Alessi Patrizia , Coltrini Daniela , Bugatti Antonella , Mitola Stefania , Nicoli Stefania , Vannini Vanio , Presta Marco
Published: April 2023

Abstract
Angiogenesis is target for antineoplastic and chemopreventive therapies. The natural phytoalexin resveratrol is found in grapes and red wine as cis and trans stereoisomers. trans-Resveratrol shows antiangiogenic activity, but its mechanism of action is not fully elucidated. Recently, trans-resveratrol has been shown to interact with the β3 integrin subunit, raising the possibility that inhibition of endothelial αvβ3 integrin function may concur to its angiosuppressive activity. To get novel insights about the antiangiogenic activity of resveratrol, we compared cis- and trans-resveratrol stereoisomers for their effect on the angiogenesis process and endothelial αvβ3 integrin function. trans-Resveratrol inhibits endothelial cell proliferation and the repair of mechanically wounded endothelial cell monolayers. Also, it prevents endothelial cell sprouting in fibrin gel, collagen gel invasion, and morphogenesis on Matrigel. In vivo, trans-resveratrol inhibits vascularization of the chick embryo area vasculosa and murine melanoma B16 tumor growth and neovascularization. In all the assays, cis-resveratrol exerts a limited, if any, effect. In keeping with these observations, trans-resveratrol, but not cis-resveratrol, inhibits αvβ3 integrin-dependent endothelial cell adhesion and the recruitment of enhanced green fluorescent protein-tagged β3 integrin in focal adhesion contacts. In conclusion, stereoisomery affects the antiangiogenic activity of resveratrol, the trans isomer being significantly more potent than the cis isoform. The different antiangiogenic potential of resveratrol stereoisomers is related, at least in part, to their different capacity to affect αvβ3 integrin function. This may have profound implications for the design of synthetic antiangiogenic/angiopreventive phytoalexin derivatives. [Mol Cancer Ther 2008;7(12):3761–70]
Data from Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells
Authors: Parsels Leslie A. , Morgan Meredith A. , Tanska Daria M. , Parsels Joshua D. , Palmer Brian D. , Booth R. John , Denny William A. , Canman Christine E. , Kraker Alan J. , Lawrence Theodore S. , Maybaum Jonathan
Published: April 2023

Abstract
The protein kinase checkpoint kinase 1 (Chk1) has been implicated as a key regulator of cell cycle progression and DNA repair, and inhibitors of Chk1 (e.g., UCN-01 and EXEL-9844) potentiate the cytotoxic actions of chemotherapeutic drugs in tumor cells. We have examined the ability of PD-321852, a small-molecule Chk1 inhibitor, to potentiate gemcitabine-induced clonogenic death in a panel of pancreatic cancer cell lines and evaluated the relationship between endpoints associated with Chk1 inhibition and chemosensitization. Gemcitabine chemosensitization by minimally toxic concentrations of PD-321852 ranged from minimal (<3-fold change in survival) in Panc1 cells to >30-fold in MiaPaCa2 cells. PD-321852 inhibited Chk1 in all cell lines as evidenced by stabilization of Cdc25A; in combination with gemcitabine, a synergistic loss of Chk1 protein was observed in the more sensitized cell lines. Gemcitabine chemosensitization, however, did not correlate with abrogation of the S-M or G2-M checkpoint; PD-321852 did not induce premature mitotic entry in gemcitabine-treated BxPC3 or M-Panc96 cells, which were sensitized to gemcitabine 6.2- and 4.6-fold, respectively. In the more sensitized cells lines, PD-321852 not only inhibited gemcitabine-induced Rad51 focus formation and the recovery from gemcitabine-induced replication stress, as evidenced by persistence of γ-H2AX, but also depleted these cells of Rad51 protein. Our data suggest the inhibition of this Chk1-mediated Rad51 response to gemcitabine-induced replication stress is an important factor in determining gemcitabine chemosensitization by Chk1 inhibition in pancreatic cancer cells. [Mol Cancer Ther 2009;8(1):45–54]
Data from Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin
Authors: Peklak-Scott Christina , Smitherman Pamela K. , Townsend Alan J. , Morrow Charles S.
Published: April 2023

Abstract
Cells expressing elevated levels of allelic variants of human glutathione S-transferase P1 (GSTP1) and/or efflux transporters, MRP1 or MRP2, were used to evaluate the role of GSTP1-1 in cisplatin resistance. These studies revealed that GSTP1-1 confers low-level resistance (1.4- to 1.7-fold) to cisplatin-induced cytotoxicity in MCF7 cells. However, expression of MRP1 (MCF7 cells) or MRP2 (HepG2 cells) failed to augment or potentiate GSTP1-1-mediated resistance in either cell line. To understand the mechanism by which variants of GSTP1-1 confer resistance to cisplatin, their relative abilities to catalyze conjugation of cisplatin with glutathione were examined. Enzymes encoded by all three alleles tested, GSTP1a (I104A113), GSTP1b (V104A113), and GSTP1c (V104V113), increased the formation rate of the mono-platinum/glutathione derivative of cisplatin with relative catalytic activities of 1.0 (GSTP1a-1a variant) and 1.8 to 1.9 (GSTP1b-1b and GSTP1c-1c variants). Although these data are consistent with the idea that very low level resistance to cisplatin may be conferred by GSTP1-1-mediated cisplatin/glutathione conjugation, two observations indicate that such catalysis plays a minor role in the protection from cisplatin toxicity. First, the rates of GSTP1-1-mediated conjugation are extremely slow (1.7-2.6 h−1 at 25°C). Second, despite an 80% to 90% increase in catalysis of cisplatin conjugation by GSTP1b-1b or GSTP1c-1c over GSTP1a-1a, we observed no discernable differences in relative resistances conferred by these alternative variants when expressed in MCF7 cells. We conclude that high-level cisplatin resistance attributed to GSTP1-1 in other studies is not likely due to catalysis of cisplatin conjugation but rather must be explained by other mechanisms, which may include GSTP1-mediated modulation of signaling pathways. [Mol Cancer Ther 2008;7(10):3247–55]
Data from Carbonic anhydrase IX has chaperone-like functions and is an immunoadjuvant
Authors: Wang Yanping , Wang Xiang-Yang , Subjeck John R. , Kim Hyung L.
Published: April 2023

Abstract
Carbonic anhydrase IX (CA9) is a hypoxia-regulated, transmembrane protein associated with neoplastic growth in a large spectrum of human tumors. CA9 is expressed in nearly all clear-cell renal tumors; levels of CA9 expression predict prognosis and response to interleukin-2 therapy. These observations may be explained by a novel chaperone-like function of CA9, which allows it to serve as an immunoadjuvant and stimulate an adaptive immune response against tumor antigens. Classic heat shock proteins (HSP) such as HSP110 and HSP70 are up-regulated in response to cellular stress and function to protect intracellular proteins from aggregation. Similarly, CA9 formed complexes with client proteins and inhibited heat-induced aggregation and enabled refolding of denatured client protein. HSP released from injured cells activate an immune response. CA9 bound dendritic cells in a receptor-specific manner. Bound CA9 was internalized by dendritic cells and processed primarily through the proteosomal pathway. In a murine melanoma model, a complex of CA9 and gp100 generated a gp100-specific antitumor response. A soluble form of CA9 shed from tumor cells had the same chaperone-like functions, providing renal tumors and hypoxic cells with a mechanism for stimulating an immune response against extracellular antigens. Interleukin-2 treatment of patient renal tumors in short-term culture increased CA9 shedding, suggesting a strategy for augmenting the immunogenicity of renal tumors. CA9 has chaperone-like functions and CA9 shed from tumors may play a direct role in stimulating an adaptive immune response. [Mol Cancer Ther 2008;7(12):3867–77]
Data from A role for macroautophagy in protection against 4-hydroxytamoxifen–induced cell death and the development of antiestrogen resistance
Authors: Samaddar Julia S. , Gaddy Virgil T. , Duplantier Jennifer , Thandavan Sudharsan Periyasamy , Shah Manish , Smith Marlena J. , Browning Darren , Rawson Jim , Smith Sylvia B. , Barrett John T. , Schoenlein Patricia V.
Published: April 2023

Abstract
This study identifies macroautophagy as a key mechanism of cell survival in estrogen receptor–positive (ER+) breast cancer cells undergoing treatment with 4-hydroxytamoxifen (4-OHT). This selective ER modifier is an active metabolite of tamoxifen commonly used for the treatment of breast cancer. Our study provides the following key findings: (a) only 20% to 25% of breast cancer cells treated with 4-OHT in vitro die via caspase-dependent cell death; more typically, the antiestrogen-treated ER+ breast cancer cells express increased levels of macroautophagy and are viable; (b) 4-OHT–induced cell death, but not 4-OHT–induced macroautophagy, can be blocked by the pan-caspase inhibitor z-VAD-fmk, providing strong evidence that these two outcomes of antiestrogen treatment are not linked in an obligatory manner; (c) 4-OHT–resistant cells selected from ER+ breast cancer cells show an increased ability to undergo antiestrogen-induced macroautophagy without induction of caspase-dependent cell death; and (d) 4-OHT, when used in combination with inhibitors of autophagosome function, induces robust, caspase-dependent apoptosis of ER+, 4-OHT–resistant breast cancer cells. To our knowledge, these studies provide the first evidence that macroautophagy plays a critical role in the development of antiestrogen resistance. We propose that targeting autophagosome function will improve the efficacy of hormonal treatment of ER+ breast cancer. [Mol Cancer Ther 2008;7(9):2977–87]
Data from Z3, a novel Jak2 tyrosine kinase small-molecule inhibitor that suppresses Jak2-mediated pathologic cell growth
Authors: Sayyah Jacqueline , Magis Andrew , Ostrov David A. , Allan Robert W. , Braylan Raul C. , Sayeski Peter P.
Published: April 2023

Abstract
Jak2 tyrosine kinase is essential for animal development and hyperkinetic Jak2 function has been linked to a host of human diseases. Control of this pathway using Jak2-specific inhibitors would therefore potentially serve as a useful research tool and/or therapeutic agent. Here, we used a high-throughput program called DOCK to predict the ability of 20,000 small molecules to interact with a structural pocket adjacent to the ATP-binding site of murine Jak2. One small molecule, 2-methyl-1-phenyl-4-pyridin-2-yl-2-(2-pyridin-2-ylethyl)butan-1-one (herein designated as Z3), bound to Jak2 with a favorable energy score. Z3 inhibited Jak2-V617F and Jak2-WT autophosphorylation in a dose-dependent manner but was not cytotoxic to cells at concentrations that inhibited kinase activity. Z3 selectively inhibited Jak2 kinase function with no effect on Tyk2 or c-Src kinase function. Z3 significantly inhibited proliferation of the Jak2-V617F-expressing, human erythroleukemia cell line, HEL 92.1.7. The Z3-mediated reduction in cell proliferation correlated with reduced Jak2 and STAT3 tyrosine phosphorylation levels as well as marked cell cycle arrest. Finally, Z3 inhibited the growth of hematopoietic progenitor cells isolated from the bone marrow of an essential thrombocythemia patient harboring the Jak2-V617F mutation and a polycythemia vera patient carrying a Jak2-F537I mutation. Collectively, the data suggest that Z3 is a novel specific inhibitor of Jak2 tyrosine kinase. [Mol Cancer Ther 2008;7(8):2308–18]
Data from Key role for Bak activation and Bak-Bax interaction in the apoptotic response to vinblastine
Authors: Upreti Meenakshi , Chu Rong , Galitovskaya Elena , Smart Sherri K. , Chambers Timothy C.
Published: April 2023

Abstract
Microtubule inhibitors such as vinblastine cause mitotic arrest and subsequent apoptosis through the intrinsic mitochondrial pathway. However, although Bcl-2 family proteins have been implicated as distal mediators, their precise role is largely unknown. In this study, we investigated the role of Bak in vinblastine-induced apoptosis. Bak was mainly monomeric in untreated KB-3 cells, and multimers corresponding to dimer, trimer, and higher oligomers were observed after vinblastine treatment. The oligomeric Bak species were strongly diminished in cells stably overexpressing Bcl-xL. Immunoprecipitation with a conformation-dependent Bak antibody revealed that vinblastine induced Bak activation. Reciprocal immunoprecipitations indicated that vinblastine induced the interaction of active Bak with active Bax. Furthermore, Bcl-xL overexpression prevented Bak and Bax interaction and strongly inhibited apoptosis, whereas Bcl-2 overexpression did not prevent Bak-Bax interaction and only weakly inhibited apoptosis. The relative contributions of Bak and Bax were investigated using fibroblasts deficient in one or both of these proteins; double knockouts were highly resistant compared with single knockouts, with vinblastine sensitivities in the order of Bak+/Bax+ > Bak+/Bax- > Bak-/Bax+ > Bak-/Bax-. These results highlight Bak as a key mediator of vinblastine-induced apoptosis and show for the first time activation and oligomerization of Bak by an antimitotic agent. In addition, our results suggest that the interaction of the activated forms of Bak and Bax represents a key distal step in the apoptotic response to this important chemotherapeutic drug. [Mol Cancer Ther 2008;7(7):2224–32]
Data from Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia
Authors: Chou C. James , Farkas Michelle E. , Tsai Sherry M. , Alvarez David , Dervan Peter B. , Gottesfeld Joel M.
Published: April 2023

Abstract
We recently identified a polyamide-chlorambucil conjugate, 1R-Chl, which alkylates and down-regulates transcription of the human histone H4c gene and inhibits the growth of several cancer cell lines in vitro and in a murine SW620 xenograft model, without apparent animal toxicity. In this study, we analyzed the effects of 1R-Chl in the chronic myelogenous leukemia cell line K562 and identified another polyamide conjugate, 6R-Chl, which targets H4 genes and elicits a similar cellular response. Other polyamide conjugates that do not target the H4 gene do not elicit this response. In a murine model, both 1R-Chl and 6R-Chl were found to be highly effective in blocking K562 xenograft growth with high-dose tolerance. Unlike conventional and distamycin-based alkylators, little or no cytotoxicities and animal toxicities were observed in mg/kg dosage ranges. These results suggest that these polyamide alkylators may be a viable treatment alternative for chronic myelogenous leukemia. [Mol Cancer Ther 2008;7(4):769–78]
Data from Coronarin D, a labdane diterpene, inhibits both constitutive and inducible nuclear factor-κB pathway activation, leading to potentiation of apoptosis, inhibition of invasion, and suppression of osteoclastogenesis
Authors: Kunnumakkara Ajaikumar B. , Ichikawa Haruyo , Anand Preetha , Mohankumar Chiramel J. , Hema Padmanabhan S. , Nair Mangalam S. , Aggarwal Bharat B.
Published: April 2023

Abstract
Compounds isolated from members of the Zingiberaceae family are traditionally used as a medicine against inflammatory diseases, but little is known about the mechanism. Here, we report the isolation and structural identification of coronarin D [E-labda-8(17),12-diene-15-ol], a labdane-type diterpene, from Hedychium coronarium and delineate its mechanism of action. Because the transcription factor nuclear factor-κB (NF-κB) is a key mediator of inflammation, apoptosis, invasion, and osteoclastogenesis, we investigated the effect of coronarin D on NF-κB activation pathway, NF-κB-regulated gene products, and NF-κB-regulated cellular responses. The coronarin D inhibited NF-κB activation induced by different inflammatory stimuli and carcinogens. This labdane also suppressed constitutive NF-κB activity in different cell lines and inhibited IκBα kinase activation, thus leading to the suppression of IκBα phosphorylation, degradation, p65 nuclear translocation, and reporter gene transcription. Coronarin D also inhibited the NF-κB-regulated gene products involved in cell survival (inhibitor of apoptosis protein 1, Bcl-2, survivin, and tumor necrosis factor receptor-associated factor-2), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of these gene products by the diterpene enhanced apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced cellular invasion, and abrogated receptor activator of NF-κB ligand-induced osteoclastogenesis. Coronarin D was found to be more potent than its analogue coronarin D acid. Overall, our results show that coronarin D inhibited NF-κB activation pathway, which leads to inhibition of inflammation, invasion, and osteoclastogenesis, as well as potentiation of apoptosis. [Mol Cancer Ther 2008;7(10):3306–17]
Data from Inhibition of fatty acid synthase by luteolin post-transcriptionally down-regulates c-Met expression independent of proteosomal/lysosomal degradation
Authors: Coleman David T. , Bigelow Rebecca , Cardelli James A.
Published: April 2023

Abstract
The hepatocyte growth factor (HGF)/c-Met signaling pathway is involved in the progression of several cancers and associated with increased tumor invasion and metastatic potential. We determined previously that the polyphenol epigallocatechin-3-gallate inhibited HGF-induced c-Met phosphorylation in a variety of tumor cell lines in part by disrupting lipid rafts. Fatty acid synthase (FASN) is implicated in cancer progression and may regulate lipid raft function. We therefore examined the effects of luteolin, a potent FASN inhibitor, on c-Met signaling. Luteolin blocked HGF-induced c-Met phosphorylation and scattering of DU145 prostate cancer cells, but inhibition required at least a 4 h preincubation time. Western blot analysis indicated that inhibition of HGF-induced scattering by luteolin occurred coincident with reduction of total c-Met protein in DU145 cells. In addition, luteolin-induced c-Met down-regulation was mimicked by a pharmacologic inhibitor of FASN, C75, or short hairpin RNA knockdown of FASN. Consistent with a role for FASN, loss of c-Met in cells treated with C75 or luteolin was prevented by exogenous addition of palmitate. Luteolin-induced loss of c-Met primarily occurred at a post-transcriptional level and involved cell surface internalization but did not involve translation inhibition, nor was it dependent on the activity of the 26S proteosome or acidic lysosomes. Taken together, our study shows a novel connection between FASN activity and c-Met protein expression and suggests that luteolin could act as a novel HGF/c-Met inhibitor by reducing expression of this receptor. [Mol Cancer Ther 2009;8(1):214–24]
Data from Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis
Authors: Stabile Laura P. , Rothstein Mary E. , Keohavong Phouthone , Jin Jide , Yin Jinling , Land Stephanie R. , Dacic Sanja , Luong The Minh , Kim K. Jin , Dulak Austin M. , Siegfried Jill M.
Published: April 2023

Abstract
The hepatocyte growth factor (HGF)/c-Met signaling pathway is involved in lung tumor growth and progression, and agents that target this pathway have clinical potential for lung cancer treatment. L2G7, a single potent anti-human HGF neutralizing monoclonal antibody, showed profound inhibition of human HGF-induced phosphorylated mitogen-activated protein kinase induction, wound healing, and invasion in lung tumor cells in vitro. Transgenic mice that overexpress human HGF in the airways were used to study the therapeutic efficacy of L2G7 for lung cancer prevention. Mice were treated with the tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, over 4 weeks. Beginning at week 3, i.p. treatment with 100 μg L2G7 or isotype-matched antibody control, 5G8, was initiated and continued through week 15. The mean number of tumors per mouse in the L2G7-treated group was significantly lower than in the control group (1.58 versus 3.19; P = 0.0005). Proliferative index was decreased by 48% (P = 0.013) in tumors from L2G7-treated mice versus 5G8-treated mice, whereas extent of apoptosis was increased in these same tumors by 5-fold (P = 0.0013). Phosphorylated mitogen-activated protein kinase expression was also significantly decreased by 84% in tumors from L2G7-treated mice versus 5G8-treated mice (P = 0.0003). Tumors that arose in HGF transgenic animals despite L2G7 treatment were more likely to contain mutant K-ras, suggesting that targeting the HGF/c-Met pathway may not be as effective if downstream signaling is activated by a K-ras mutation. These preclinical results show that blocking the HGF/c-Met interaction with a single monoclonal antibody delivered systemically can have profound inhibitory effects on development of lung tumors. [Mol Cancer Ther 2008;7(7):1913–22]
Data from Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model
Authors: Miyanaga Akihiko , Gemma Akihiko , Noro Rintaro , Kataoka Kiyoko , Matsuda Kuniko , Nara Michiya , Okano Tetsuya , Seike Masahiro , Yoshimura Akinobu , Kawakami Akiko , Uesaka Haruka , Nakae Hiroki , Kudoh Shoji
Published: April 2023

Abstract
To ascertain the potential for histone deacetylase (HDAC) inhibitor-based treatment in non-small cell lung cancer (NSCLC), we analyzed the antitumor effects of trichostatin A (TSA) and suberoylanilide hydroxamic acid (vorinostat) in a panel of 16 NSCLC cell lines via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. TSA and vorinostat both displayed strong antitumor activities in 50% of NSCLC cell lines, suggesting the need for the use of predictive markers to select patients receiving this treatment. There was a strong correlation between the responsiveness to TSA and vorinostat (P < 0.0001). To identify a molecular model of sensitivity to HDAC inhibitor treatment in NSCLC, we conducted a gene expression profiling study using cDNA arrays on the same set of cell lines and related the cytotoxic activity of TSA to corresponding gene expression pattern using a modified National Cancer Institute program. In addition, pathway analysis was done with Pathway Architect software. We used nine genes, which were identified by gene-drug sensitivity correlation and pathway analysis, to build a support vector machine algorithm model by which sensitive cell lines were distinguished from resistant cell lines. The prediction performance of the support vector machine model was validated by an additional nine cell lines, resulting in a prediction value of 100% with respect to determining response to TSA and vorinostat. Our results suggested that (a) HDAC inhibitors may be promising anticancer drugs to NSCLC and (b) the nine-gene classifier is useful in predicting drug sensitivity to HDAC inhibitors and may contribute to achieving individualized therapy for NSCLC patients. [Mol Cancer Ther 2008;7(7):1923–30]
Data from Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes
Authors: Lang Sven A. , Schachtschneider Philipp , Moser Christian , Mori Akira , Hackl Christina , Gaumann Andreas , Batt David , Schlitt Hans J. , Geissler Edward K. , Stoeltzing Oliver
Published: April 2023

Abstract
The Ras/Raf/MEK pathway represents an important oncogenic signaling pathway in gastrointestinal malignancies, including pancreatic cancer. Although activating B-Raf mutations are infrequent in pancreatic cancer, we hypothesized that targeting Raf could be valuable for therapy of this cancer entity. Moreover, as vascular endothelial growth factor receptor 2 (VEGFR2) is involved in tumor angiogenesis, we sought to investigate the effects of dual inhibition of Raf and VEGFR2 on pancreatic tumor growth, vascularization, and metastasis. Effects of a Raf/VEGFR2 inhibitor (NVP-AAL881) on pancreatic cancer cells, endothelial cells, and vascular smooth muscle cells were determined by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and migration assays, respectively. Changes in the expression of VEGF-A or survivin were investigated by ELISA and/or real-time PCR. The growth-inhibitory effects of Raf/VEGFR2 inhibition were additionally evaluated in orthotopic tumor models. Results showed that various Raf isoforms were activated in pancreatic cancer cells and NVP-AAL881 diminished the activation of MEK, Akt, Erk, and also STAT3. Moreover, dual inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and SAPK phosphorylation in endothelial cells, the Raf inhibitor diminished STAT3 phosphorylation, independent of a VEGFR2 blockade, and reduced the expression of survivin. In addition, cell proliferation and migration of both endothelial cells and vascular smooth muscle cells were significantly reduced. In vivo, blocking Raf/VEGFR2 significantly inhibited orthotopic tumor growth and vascularization and reduced cancer metastasis. In conclusion, blocking Raf exerts growth-inhibitory effects on pancreatic tumor cells, endothelial cells, and pericytes and elicits antiangiogenic properties. Dual targeting of Raf and VEGFR2 appears to be a valid strategy for therapy of pancreatic cancer. [Mol Cancer Ther 2008;7(11):3509–18]
Data from PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer
Authors: Carpinelli Patrizia , Ceruti Roberta , Giorgini Maria Laura , Cappella Paolo , Gianellini Laura , Croci Valter , Degrassi Anna , Texido Gemma , Rocchetti Maurizio , Vianello Paola , Rusconi Luisa , Storici Paola , Zugnoni Paola , Arrigoni Claudio , Soncini Chiara , Alli Cristina , Patton Veronica , Marsiglio Aurelio , Ballinari Dario , Pesenti Enrico , Fancelli Daniele , Moll Jürgen
Published: April 2023

Abstract
PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition–related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status–dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser10 is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers. [Mol Cancer Ther 2007;6(12):3158–68]
Data from Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts
Authors: Di Cello Francescopaolo , Hillion Joelle , Kowalski Jeanne , Ronnett Brigitte M. , Aderinto Abimbola , Huso David L. , Resar Linda M.S.
Published: April 2023

Abstract
Uterine cancer is a common cause for cancer death in women and there is no effective therapy for metastatic disease. Thus, research is urgently needed to identify new therapeutic agents. We showed previously that all female HMGA1a transgenic mice develop malignant uterine tumors, indicating that HMGA1a causes uterine cancer in vivo. We also demonstrated that HMGA1a up-regulates cyclooxygenase-2 (COX-2) during tumorigenesis in this model. Similarly, we found that HMGA1a and COX-2 are overexpressed in human leiomyosarcomas, a highly malignant uterine cancer. Although epidemiologic studies indicate that individuals who take COX inhibitors have a lower incidence of some tumors, these inhibitors have not been evaluated in uterine cancer. Here, we show that HMGA1a mice on sulindac (a COX-1/COX-2 inhibitor) have significantly smaller uterine tumors than controls. To determine if COX inhibitors are active in human uterine cancers that overexpress HMGA1a, we treated cultured cells with sulindac sulfide or celecoxib (a specific COX-2 inhibitor). Both drugs block anchorage-independent growth in high-grade human uterine cancer cells that overexpress HMGA1a (MES-SA cells). In contrast, neither inhibitor blocked transformation in cells that do not overexpress HMGA1a. Moreover, xenograft tumors from MES-SA cells were significantly inhibited in mice on sulindac. More strikingly, no tumors formed in mice on celecoxib. These preclinical studies suggest that COX inhibitors could play a role in preventing tumor onset or progression in uterine cancers with dysregulation of the HMGA1a-COX-2 pathway. Importantly, these drugs have lower toxicity than chemotherapeutic agents used to treat advanced-stage uterine cancers. [Mol Cancer Ther 2008;7(7):2090–5]
Data from Asparagine synthetase is a predictive biomarker of l-asparaginase activity in ovarian cancer cell lines
Authors: Lorenzi Philip L. , Llamas Jenny , Gunsior Michele , Ozbun Laurent , Reinhold William C. , Varma Sudhir , Ji Helen , Kim Hijoo , Hutchinson Amy A. , Kohn Elise C. , Goldsmith Paul K. , Birrer Michael J. , Weinstein John N.
Published: April 2023

Abstract
We recently used RNA interference to show that a negative correlation of l-asparaginase (l-ASP) chemotherapeutic activity with asparagine synthetase (ASNS) expression in the ovarian subset of the NCI-60 cell line panel is causal. To determine whether that relationship would be sustained in a larger, more diverse set of ovarian cell lines, we have now measured ASNS mRNA expression using microarrays and a branched-DNA RNA assay, ASNS protein expression using an electrochemiluminescent immunoassay, and l-ASP activity using an MTS assay on 19 human ovarian cancer cell lines. Contrary to our previous findings, l-ASP activity was only weakly correlated with ASNS mRNA expression; Pearson's correlation coefficients were r = -0.21 for microarray data and r = -0.39 for the branched-DNA RNA assay, with just the latter being marginally statistically significant (P = 0.047, one-tailed). ASNS protein expression measured by liquid-phase immunoassay exhibited a much stronger correlation (r = -0.65; P = 0.0014, one-tailed). We conclude that ASNS protein expression measured by immunoassay is a strong univariate predictor of l-ASP activity in ovarian cancer cell lines. These findings provide rationale for evaluation of ASNS protein expression as a predictive biomarker of clinical l-ASP activity in ovarian cancer. [Mol Cancer Ther 2008;7(10):3123–8]