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Papers by Lizbeth Lockwood
Cancer Research
Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes approximately 50% of ... more Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes approximately 50% of affected individuals to develop plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs) in approximately 10% of patients. NF1 is caused by mutations in the tumor suppressor gene NF1, which encodes for neurofibromin, a negative regulator of RAS activity. Selumetinib, a specific inhibitor of MEK1/2, is the only FDA-approved drug for NF1-associated PNFs. However, the anti-tumor effects of selumetinib are limited in MPNSTs and have dose-limiting side effects. Deficiency of the NF1 gene not only promotes tumorigenesis but also has broad effects on the immune cells and cytokine signaling driven by hyperactive RAS signaling. Because macrophages account for almost half of cells in NF1 lesions and their infiltration highly correlates with disease progression, we hypothesized that targeting tumor-promoting immune cells could be an a...
Pediatrics, 2018
Purpose: Injury to the intestinal mucosa with loss of epithelial barrier integrity is a pathophys... more Purpose: Injury to the intestinal mucosa with loss of epithelial barrier integrity is a pathophysiologic hallmark of necrotizing enterocolitis (NEC). Several key mediators of gastrointestinal wound healing have been identified including prostanoids synthesized via cyclooxygenase 2 (COX-2). 5-hydroxytryptamine (5-HT, serotonin) may also regulate wound healing as recent evidence suggests that 5-HT is a pro-inflammatory paracrine signaling molecule. Intestinal mucosal 5-HT is synthesized in the enterochromaffin (EC) cell from tryptophan by tryptophan hydroxylase type 1 (TPH1). 5-HT is released from the EC cell and its clearance and extracellular levels …
Necrotizing enterocolitis (NEC) is an inflammatory disease of the intestine primarily affecting p... more Necrotizing enterocolitis (NEC) is an inflammatory disease of the intestine primarily affecting preterm infants. Currently, the diagnosis of NEC is based on a constellation of non-specific clinical symptoms and signs, radiologic findings, and laboratory data (Bell's staging criteria). However, a definitive diagnosis of NEC is difficult because of its similarity in presentation to other clinical conditions. Biomarkers measured in stool samples will better reflect inflammation and pathology specific to the intestine. Certain stool markers are able to identify inflammatory bowel disease in pediatric and …
Scientific Reports, 2021
Mutations in BRCA genes are the leading cause of hereditary breast cancer. Current options to pre... more Mutations in BRCA genes are the leading cause of hereditary breast cancer. Current options to prevent cancer in these high-risk patients, such as anti-estrogen drugs and radical mastectomy, are limited by lack of efficacy, undesirable toxicities, or physical and emotional challenges. We have previously shown that PARP inhibitors can significantly delay tumor development in BRCA1-deficient mice. Here, we fabricated the PARP inhibitor talazoparib (TLZ) into spacer implants (InCeT-TLZ) for localized and sustained delivery. We hypothesized that this novel formulation will provide an effective chemopreventive strategy with minimal toxicity. TLZ was released gradually over 30 days as implants degraded. InCeT-TLZ significantly decreased proliferation and increased DNA damage in the mammary glands of BRCA1-deficient mice. Notably, the number of mice that developed hyperplasia in the mammary glands was significantly lower with InCeT-TLZ treatment compared to the control group. Meanwhile, InC...
Molecular Cancer Therapeutics, 2021
The nuclear factor erythroid-2-related factor 2 (Nrf2)–Keap1–ARE pathway, a master regulator of o... more The nuclear factor erythroid-2-related factor 2 (Nrf2)–Keap1–ARE pathway, a master regulator of oxidative stress, has emerged as a promising target for cancer therapy. Mutations in NFE2L2, KEAP1, and related genes have been found in many human cancers, especially lung cancer. These mutations lead to constitutive activation of the Nrf2 pathway, which promotes proliferation of cancer cells and their resistance to chemotherapies. Small molecules that inhibit the Nrf2 pathway are needed to arrest tumor growth and overcome chemoresistance in Nrf2-addicted cancers. Here, we identified a novel small molecule, MSU38225, which can suppress Nrf2 pathway activity. MSU38225 downregulates Nrf2 transcriptional activity and decreases the expression of Nrf2 downstream targets, including NQO1, GCLC, GCLM, AKR1C2, and UGT1A6. MSU38225 strikingly decreases the protein level of Nrf2, which can be blocked by the proteasome inhibitor MG132. Ubiquitination of Nrf2 is enhanced following treatment with MSU3...
Cancer Research, 2020
Mutations in BRCA genes are the leading cause of hereditary breast cancer and dramatically increa... more Mutations in BRCA genes are the leading cause of hereditary breast cancer and dramatically increase the lifetime risk of developing breast cancer. Anti-estrogen drugs are approved to reduce the risk of developing invasive breast cancer, but they are not effective for women with germline BRCA mutations and are limited by undesirable toxicities. Radical mastectomy provides a surgical option for high-risk patients for cancer prevention, but the physical and emotional challenges of such a radical surgery confirm that alternative approaches are needed. Our goal is to develop novel chemopreventive agents that are effective and safe for BRCA carriers. PARP inhibitors are effective for treating BRCA-mutated breast cancer patients, and we have shown that these drugs significantly delayed tumor development in BRCA-deficient mice. Here, we developed a novel implantable formulation of the PARP inhibitor Talazoparib for local delivery and thus provide a new therapeutic strategy for prevention of...
Physiological reports, 2014
Large conductance Ca(2+)-activated K(+) (BK) channels consist of pore-forming α- and accessory β-... more Large conductance Ca(2+)-activated K(+) (BK) channels consist of pore-forming α- and accessory β-subunits. There are four β-subunit subtypes (β1-β4), BK β1-subunit is specific for smooth muscle cells (SMC). Reduced BK β1-subunit expression is associated with SMC dysfunction in animal models of human disease, because downregulation of BK β1-subunit reduces channel activity and increases SMC contractility. Several anti-BK β1-subunit antibodies are commercially available; however, the specificity of most antibodies has not been tested or confirmed in the tissues from BK β1-subunit knockout (KO) mice. In this study, we tested the specificity and sensitivity of six commercially available antibodies from five manufacturers. We performed western blot analysis on BK β1-subunit enriched tissues (mesenteric arteries and colons) and non-SM tissue (cortex of kidney) from wild-type (WT) and BK β1-KO mice. We found that antibodies either detected protein bands of the appropriate molecular weight ...
Gastroenterology, 2010
Role of TNF-α in the Pathogenesis of Indomethacin-Induced Small Intestinal Injury in Mice Kohei F... more Role of TNF-α in the Pathogenesis of Indomethacin-Induced Small Intestinal Injury in Mice Kohei Fukumoto, Yuji Naito, Tomohisa Takagi, Shinya Yamada, Ryusuke Horie, Ken Inoue, Akihito Harusato, Ikuhiro Hirata, Tatsushi Omatsu, Etsuko Kishimoto, Katsura Mizushima, Yasuko Hirai, Kazuhiko Uchiyama, Takeshi Ishikawa, Osamu Handa, Hideyuki Konishi, Naoki Wakabayashi, Nobuaki Yagi, Satoshi Kokura, Hiroshi Ichikawa, Masakazu Kita, Toshikazu Yoshikawa
Biochemistry (Moscow), 2004
We have studied the effect of polycyclic aromatic hydrocarbons (PAH) on gap junction intercellula... more We have studied the effect of polycyclic aromatic hydrocarbons (PAH) on gap junction intercellular communica tions (GJIC) in culture of hepatoma cells Hep G2 and G27. Carcinogenic PAH inhibited GJIC in both cultures in contrast to non carcinogenic PAH. We showed that both constitutive and inducible expressions of mRNAs of Ah receptor and cytochrome P4501A1 (the main isoform involved in PAH metabolism) were absent in hepatoma G27 cells. We concluded that the initial, non metabolized molecules of carcinogenic PAH are responsible for changes in GJIC through interaction with an unknown factor in the cellular membrane.
Cancer Research
Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes approximately 50% of ... more Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes approximately 50% of affected individuals to develop plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs) in approximately 10% of patients. NF1 is caused by mutations in the tumor suppressor gene NF1, which encodes for neurofibromin, a negative regulator of RAS activity. Selumetinib, a specific inhibitor of MEK1/2, is the only FDA-approved drug for NF1-associated PNFs. However, the anti-tumor effects of selumetinib are limited in MPNSTs and have dose-limiting side effects. Deficiency of the NF1 gene not only promotes tumorigenesis but also has broad effects on the immune cells and cytokine signaling driven by hyperactive RAS signaling. Because macrophages account for almost half of cells in NF1 lesions and their infiltration highly correlates with disease progression, we hypothesized that targeting tumor-promoting immune cells could be an a...
Pediatrics, 2018
Purpose: Injury to the intestinal mucosa with loss of epithelial barrier integrity is a pathophys... more Purpose: Injury to the intestinal mucosa with loss of epithelial barrier integrity is a pathophysiologic hallmark of necrotizing enterocolitis (NEC). Several key mediators of gastrointestinal wound healing have been identified including prostanoids synthesized via cyclooxygenase 2 (COX-2). 5-hydroxytryptamine (5-HT, serotonin) may also regulate wound healing as recent evidence suggests that 5-HT is a pro-inflammatory paracrine signaling molecule. Intestinal mucosal 5-HT is synthesized in the enterochromaffin (EC) cell from tryptophan by tryptophan hydroxylase type 1 (TPH1). 5-HT is released from the EC cell and its clearance and extracellular levels …
Necrotizing enterocolitis (NEC) is an inflammatory disease of the intestine primarily affecting p... more Necrotizing enterocolitis (NEC) is an inflammatory disease of the intestine primarily affecting preterm infants. Currently, the diagnosis of NEC is based on a constellation of non-specific clinical symptoms and signs, radiologic findings, and laboratory data (Bell's staging criteria). However, a definitive diagnosis of NEC is difficult because of its similarity in presentation to other clinical conditions. Biomarkers measured in stool samples will better reflect inflammation and pathology specific to the intestine. Certain stool markers are able to identify inflammatory bowel disease in pediatric and …
Scientific Reports, 2021
Mutations in BRCA genes are the leading cause of hereditary breast cancer. Current options to pre... more Mutations in BRCA genes are the leading cause of hereditary breast cancer. Current options to prevent cancer in these high-risk patients, such as anti-estrogen drugs and radical mastectomy, are limited by lack of efficacy, undesirable toxicities, or physical and emotional challenges. We have previously shown that PARP inhibitors can significantly delay tumor development in BRCA1-deficient mice. Here, we fabricated the PARP inhibitor talazoparib (TLZ) into spacer implants (InCeT-TLZ) for localized and sustained delivery. We hypothesized that this novel formulation will provide an effective chemopreventive strategy with minimal toxicity. TLZ was released gradually over 30 days as implants degraded. InCeT-TLZ significantly decreased proliferation and increased DNA damage in the mammary glands of BRCA1-deficient mice. Notably, the number of mice that developed hyperplasia in the mammary glands was significantly lower with InCeT-TLZ treatment compared to the control group. Meanwhile, InC...
Molecular Cancer Therapeutics, 2021
The nuclear factor erythroid-2-related factor 2 (Nrf2)–Keap1–ARE pathway, a master regulator of o... more The nuclear factor erythroid-2-related factor 2 (Nrf2)–Keap1–ARE pathway, a master regulator of oxidative stress, has emerged as a promising target for cancer therapy. Mutations in NFE2L2, KEAP1, and related genes have been found in many human cancers, especially lung cancer. These mutations lead to constitutive activation of the Nrf2 pathway, which promotes proliferation of cancer cells and their resistance to chemotherapies. Small molecules that inhibit the Nrf2 pathway are needed to arrest tumor growth and overcome chemoresistance in Nrf2-addicted cancers. Here, we identified a novel small molecule, MSU38225, which can suppress Nrf2 pathway activity. MSU38225 downregulates Nrf2 transcriptional activity and decreases the expression of Nrf2 downstream targets, including NQO1, GCLC, GCLM, AKR1C2, and UGT1A6. MSU38225 strikingly decreases the protein level of Nrf2, which can be blocked by the proteasome inhibitor MG132. Ubiquitination of Nrf2 is enhanced following treatment with MSU3...
Cancer Research, 2020
Mutations in BRCA genes are the leading cause of hereditary breast cancer and dramatically increa... more Mutations in BRCA genes are the leading cause of hereditary breast cancer and dramatically increase the lifetime risk of developing breast cancer. Anti-estrogen drugs are approved to reduce the risk of developing invasive breast cancer, but they are not effective for women with germline BRCA mutations and are limited by undesirable toxicities. Radical mastectomy provides a surgical option for high-risk patients for cancer prevention, but the physical and emotional challenges of such a radical surgery confirm that alternative approaches are needed. Our goal is to develop novel chemopreventive agents that are effective and safe for BRCA carriers. PARP inhibitors are effective for treating BRCA-mutated breast cancer patients, and we have shown that these drugs significantly delayed tumor development in BRCA-deficient mice. Here, we developed a novel implantable formulation of the PARP inhibitor Talazoparib for local delivery and thus provide a new therapeutic strategy for prevention of...
Physiological reports, 2014
Large conductance Ca(2+)-activated K(+) (BK) channels consist of pore-forming α- and accessory β-... more Large conductance Ca(2+)-activated K(+) (BK) channels consist of pore-forming α- and accessory β-subunits. There are four β-subunit subtypes (β1-β4), BK β1-subunit is specific for smooth muscle cells (SMC). Reduced BK β1-subunit expression is associated with SMC dysfunction in animal models of human disease, because downregulation of BK β1-subunit reduces channel activity and increases SMC contractility. Several anti-BK β1-subunit antibodies are commercially available; however, the specificity of most antibodies has not been tested or confirmed in the tissues from BK β1-subunit knockout (KO) mice. In this study, we tested the specificity and sensitivity of six commercially available antibodies from five manufacturers. We performed western blot analysis on BK β1-subunit enriched tissues (mesenteric arteries and colons) and non-SM tissue (cortex of kidney) from wild-type (WT) and BK β1-KO mice. We found that antibodies either detected protein bands of the appropriate molecular weight ...
Gastroenterology, 2010
Role of TNF-α in the Pathogenesis of Indomethacin-Induced Small Intestinal Injury in Mice Kohei F... more Role of TNF-α in the Pathogenesis of Indomethacin-Induced Small Intestinal Injury in Mice Kohei Fukumoto, Yuji Naito, Tomohisa Takagi, Shinya Yamada, Ryusuke Horie, Ken Inoue, Akihito Harusato, Ikuhiro Hirata, Tatsushi Omatsu, Etsuko Kishimoto, Katsura Mizushima, Yasuko Hirai, Kazuhiko Uchiyama, Takeshi Ishikawa, Osamu Handa, Hideyuki Konishi, Naoki Wakabayashi, Nobuaki Yagi, Satoshi Kokura, Hiroshi Ichikawa, Masakazu Kita, Toshikazu Yoshikawa
Biochemistry (Moscow), 2004
We have studied the effect of polycyclic aromatic hydrocarbons (PAH) on gap junction intercellula... more We have studied the effect of polycyclic aromatic hydrocarbons (PAH) on gap junction intercellular communica tions (GJIC) in culture of hepatoma cells Hep G2 and G27. Carcinogenic PAH inhibited GJIC in both cultures in contrast to non carcinogenic PAH. We showed that both constitutive and inducible expressions of mRNAs of Ah receptor and cytochrome P4501A1 (the main isoform involved in PAH metabolism) were absent in hepatoma G27 cells. We concluded that the initial, non metabolized molecules of carcinogenic PAH are responsible for changes in GJIC through interaction with an unknown factor in the cellular membrane.