Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorour... more Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorouracil (5-FU) is the therapy of choice for CRC, but it exhibits high toxicity and drug resistance. Tumorigenesis is characterized by a deregulated metabolism, which promotes cancer cell growth and survival. The pentose phosphate pathway (PPP) is required for the synthesis of ribonucleotides and the regulation of reactive oxygen species and is upregulated in CRC. Mannose was recently reported to halt tumor growth and impair the PPP. Mannose inhibitory effects on tumor growth are inversely related to the levels of phosphomannose isomerase (PMI). An in silico analysis showed low PMI levels in human CRC tissues. We, therefore, investigated the effect of mannose alone or in combination with 5-FU in human CRC cell lines with different p53 and 5-FU resistance statuses. Mannose resulted in a dose-dependent inhibition of cell growth and synergized with 5-FU treatment in all tested cancer cell lines...
The increased global prevalence of metabolic disorders including obesity, insulin resistance, met... more The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it b...
Emerging evidence links periprostatic adipose tissue (PPAT) inflammation, a consequence of metabo... more Emerging evidence links periprostatic adipose tissue (PPAT) inflammation, a consequence of metabolic impairment, and certain features of prostate cancer (PCa) aggressiveness. AT thromboinflammation, mediated by the proteolytic activation of protease‐activated receptors (PARs) particularly by thrombin and Factor Xa (FXa), drives AT dysfunction. Nevertheless, the contribution of PPAT thromboinflammation to early prostatic neoplastic alterations has not been investigated. Here, we utilized a non‐obese prediabetic rat model to assess prostatic neoplasia in association with PPAT thromboinflammation. Mild hypercaloric diet (MHC)‐fed rats exhibited hyperinsulinemia, hypertriglyceridemia, a lower metabolic efficiency, and a higher fat/lean ratio in comparison to regular chow‐fed rats. When compared to regular chow‐fed rats, MHC‐fed rats exhibited PPAT with larger adipocytes, enhanced oxidative stress and increased immune cell influx. Concurrently, prostates from MHC‐fed rats displayed highe...
Hybrid molecules targeting simultaneously DNA polymerase α (POLA1) and histone deacetylases (HDAC... more Hybrid molecules targeting simultaneously DNA polymerase α (POLA1) and histone deacetylases (HDACs) were designed and synthesized to exploit a potential synergy of action. Among a library of screened molecules, MIR002 and GEM144 showed antiproliferative activity at nanomolar concentrations on a panel of human solid and haematological cancer cell lines. In vitro functional assays confirmed that these molecules inhibited POLA1 primer extension activity, as well as HDAC11. Molecular docking studies also supported these findings. Mechanistically, MIR002 and GEM144 induced acetylation of p53, activation of p21, G1/S cell cycle arrest, and apoptosis. Oral administration of these inhibitors confirmed their antitumor activity in in vivo models. In human non-small cancer cell (H460) xenografted in nude mice MIR002 at 50 mg/kg, Bid (qd × 5 × 3w) inhibited tumor growth (TGI = 61%). More interestingly, in POLA1 inhibitor resistant cells (H460-R9A), the in vivo combination of MIR002 with cisplatin showed an additive antitumor effect with complete disappearance of tumor masses in two animals at the end of the treatment. Moreover, in two human orthotopic malignant pleural mesothelioma xenografts (MM473 and MM487), oral treatments with MIR002 and GEM144 confirmed their significant antitumor activity (TGI = 72-77%). Consistently with recent results that have shown an inverse correlation between POLA1 expression and type I interferon levels, MIR002 significantly upregulated interferon-α in immunocompetent mice.
ABSTRACTBackgroundVitamin A deficiency increases susceptibility to infection caused by impaired i... more ABSTRACTBackgroundVitamin A deficiency increases susceptibility to infection caused by impaired immune function.ObjectivesWe investigated whether immunodeficiency could facilitate the development of vitamin A deficiency.MethodsVitamin A deficiency was followed in 2 mouse models of immunodeficiency: the athymic nude mouse (nu/nu) and the humoral immunodeficient SENCAR (SENsitive to CARcinogenesis) mouse. Vitamin A deficiency was also monitored in outbred Balb/c and in NIH mice. The monitoring of vitamin A deficiency was done after feeding the mice and their mothers a semisynthetic, vitamin A–deficient diet from birth of the experimental mice. These mice were weaned onto the same deficient diet at 3–4 wk of age, while control groups were fed the same diet containing 3 μg retinoic acid per gram of diet.ResultsThe immunodeficient nu/nu and SENCAR mice developed vitamin A deficiency earlier than either the heterozygous nu/+ controls or the Balb/c and NIH strains. In female mice, symptoms...
To study the contribution of autocrine and paracrine TGF-beta 1 to tumor progression in a well-de... more To study the contribution of autocrine and paracrine TGF-beta 1 to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-beta 1 gene were initiated in vitro with the v-rasHa oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v-rasHa-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well-differentiated papillomas. Malignant progression was not associated with mutations in the c-rasHa gene, alterations in p53 protein, or loss of responsiveness to TGF-beta 1. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling ind...
Epigenetic mechanisms comprising DNA methylation, histone modifications, and noncoding RNAs affec... more Epigenetic mechanisms comprising DNA methylation, histone modifications, and noncoding RNAs affect chromatin structure and regulate gene expression. These mechanisms control normal embryonic development and adult life and their deregulation contributes to several diseases including cancer. The process of tumorigenesis is complex and results from the evolution of different "hallmarks of cancer". Hanahan and Weinberg presented in 2000 and 2011 seminal contributions in the cancer field, first the six hallmarks of cancer and a decade later two additional hallmarks and two enabling characteristics were added. Here, we surmise that epigenetic mechanisms regulate and contribute to every single hallmark in cancer, and thus represent the hallmark of hallmarks in tumorigenesis. Focusing on epigenetics as a major hallmark in cancer formation has profound preventive, therapeutic, and clinical implications.
Terpenoids are the largest class of natural products, most of which are derived from plants. Amon... more Terpenoids are the largest class of natural products, most of which are derived from plants. Amongst their numerous biological properties, their anti-tumor effects are of interest for they are extremely diverse which include anti-proliferative, apoptotic, anti-angiogenic, and anti-metastatic activities. Recently, several in vitro and in vivo studies have been dedicated to understanding the 'terpenoid induced autophagy' phenomenon in cancer cells. Light has already been shed on the intricacy of apoptosis and autophagy relationship. This latter crosstalk is driven by the delicate balance between activating or silencing of certain proteins whereby the outcome is expressed via interrelated signaling pathways. In this review, we focus on nine of the most studied terpenoids and on their cell death and autophagic activity. These terpenoids are grouped in three classes: sesquiterpenoid (artemisinin, parthenolide), diterpenoids (oridonin, triptolide), and triterpenoids (alisol, betulinic acid, oleanolic acid, platycodin D, and ursolic acid). We have selected these nine terpenoids among others as they belong to the different major classes of terpenoids and our extensive search of the literature indicated that they were the most studied in terms of autophagy in cancer. These terpenoids alone demonstrate the complexity by which these secondary metabolites induce autophagy via complex signaling pathways such as MAPK/ERK/JNK, PI3K/AKT/mTOR, AMPK, NF-kB, and reactive oxygen species. Moreover, induction of autophagy can be either destructive or protective in tumor cells. Nevertheless, should this phenomenon be well understood, we ought to be able to exploit it to create novel therapies and design more effective regimens in the management and treatment of cancer.
Background: Tumorigenesis is associated with deregulation of nutritional requirements, intermedia... more Background: Tumorigenesis is associated with deregulation of nutritional requirements, intermediary metabolites production, and microenvironment interactions. Unlike their normal cell counterparts, tumor cells rely on aerobic glycolysis, through the Warburg effect. Summary: The pentose phosphate pathway (PPP) is a major glucose metabolic shunt that is upregulated in cancer cells. The PPP comprises an oxidative and a nonoxidative phase and is essential for nucleotide synthesis of rapidly dividing cells. The PPP also generates nicotinamide adenine dinucleotide phosphate, which is required for reductive metabolism and to counteract oxidative stress in tumor cells. This article reviews the regulation of the PPP and discusses inhibitors that target its main pathways. Key Message: Exploiting the metabolic vulnerability of the PPP offers potential novel therapeutic opportunities and improves patients’ response to cancer therapy.
15 Regulation of Epithelial Differentiation by Retinoids Dean Rosenthal,* Francesca Lancillotti, ... more 15 Regulation of Epithelial Differentiation by Retinoids Dean Rosenthal,* Francesca Lancillotti, Nadine Darwiche, Rashmi Sinha, and Luigi M. De Luca National Cancer Institute, National Institutes of Health, Bethesda, Maryland I. INTRODUCTION Retinoids control ...
Acute myeloid leukemia (AML) is one of the most frequent, complex, and heterogeneous hematologica... more Acute myeloid leukemia (AML) is one of the most frequent, complex, and heterogeneous hematological malignancies. AML prognosis largely depends on acquired cytogenetic, epigenetic, and molecular abnormalities. Despite the improvement in understanding the biology of AML, survival rates remain quite low. Animal models offer a valuable tool to recapitulate different AML subtypes, and to assess the potential role of novel and known mutations in disease progression. This review provides a comprehensive and critical overview of select available AML animal models. These include the non-mammalian Zebrafish and Drosophila models as well as the mammalian rodent systems, comprising rats and mice. The suitability of each animal model, its contribution to the advancement of knowledge in AML pathophysiology and treatment, as well as its advantages and limitations are discussed. Despite some limitations, animal models represent a powerful approach to assess toxicity, and permit the design of new th...
Despite advances in therapeutic strategies, colorectal cancer (CRC) remains the third cause of ca... more Despite advances in therapeutic strategies, colorectal cancer (CRC) remains the third cause of cancer-related deaths with a relatively low survival rate. Resistance to standard chemotherapy represents a major hurdle in disease management; therefore, developing new therapeutic agents demands a thorough understanding of their mechanisms of action. One of these compounds is ST1926, an adamantyl retinoid that has shown potent antitumor activities in several human cancer models. Here, we show that ST1926 selectively suppressed the proliferation of CRC cells while sparing normal counterparts, and significantly reduced tumor volume in a xenograft cancer mouse model. Next, we investigated the effects of ST1926 in CRC cells and observed early DNA damage, S-phase arrest, dissipation of mitochondrial membrane potential, and apoptosis induction, in a p53 and p21-independent manner. To address the underlying mechanism of resistance to ST1926, we generated ST1926-resistant HCT116 cells and sequen...
The sesquiterpene lactone parthenolide is a major component of the feverfew medicinal plant, Tana... more The sesquiterpene lactone parthenolide is a major component of the feverfew medicinal plant, Tanacetum parthenium. Parthenolide has been extensively studied for its anti‐inflammatory and anticancer properties in several tumor models. Parthenolide's antitumor activities depend on several mechanisms but it is mainly known as an inhibitor of the nuclear factor‐κB (NF‐κB) pathway. This pathway is constitutively activated and induces cell survival in primary effusion lymphoma (PEL), a rare aggressive AIDS‐related lymphoproliferative disorder that is commonly caused by the human herpesvirus 8 (HHV‐8) infection. The aim of this study is to evaluate the targeted effect of Parthenolide both in vitro and in vivo. Herein, parthenolide significantly inhibited cell growth, induced G0/G1 cell cycle arrest, and induced massive apoptosis in PEL cells and ascites. In addition, parthenolide inhibited the NF‐ĸB pathway suppressing IĸB phosphorylation and p65 nuclear translocation. It also reduced ...
Ceramide (Cer) is a bioactive cellular lipid with compartmentalized and tightly regulated levels.... more Ceramide (Cer) is a bioactive cellular lipid with compartmentalized and tightly regulated levels. Distinct metabolic pathways lead to the generation of Cer species with distinguishable roles in oncogenesis. Deregulation of Cer pathways has emerged as an important mechanism for acquired chemotherapeutic resistance. Adult T-cell leukemia (ATL) cells are defective in Cer synthesis. ATL is an aggressive neoplasm that develops following infection with human T-cell lymphotropic virus-1 (HTLV-1) where the viral oncogene Tax contributes to the pathogenesis of the disease. ATL cells, resistant to all-trans-retinoic acid, are sensitive to pharmacologically achievable concentrations of the synthetic retinoid ST1926. We studied the effects of ST1926 on Cer pathways in ATL cells. ST1926 treatment resulted in early Tax oncoprotein degradation in HTLV-1-treated cells. ST1926 induced cell death and a dose- and time-dependent accumulation of Cer in malignant T cells. The kinetics and degree of Cer p...
Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorour... more Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorouracil (5-FU) is the therapy of choice for CRC, but it exhibits high toxicity and drug resistance. Tumorigenesis is characterized by a deregulated metabolism, which promotes cancer cell growth and survival. The pentose phosphate pathway (PPP) is required for the synthesis of ribonucleotides and the regulation of reactive oxygen species and is upregulated in CRC. Mannose was recently reported to halt tumor growth and impair the PPP. Mannose inhibitory effects on tumor growth are inversely related to the levels of phosphomannose isomerase (PMI). An in silico analysis showed low PMI levels in human CRC tissues. We, therefore, investigated the effect of mannose alone or in combination with 5-FU in human CRC cell lines with different p53 and 5-FU resistance statuses. Mannose resulted in a dose-dependent inhibition of cell growth and synergized with 5-FU treatment in all tested cancer cell lines...
The increased global prevalence of metabolic disorders including obesity, insulin resistance, met... more The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it b...
Emerging evidence links periprostatic adipose tissue (PPAT) inflammation, a consequence of metabo... more Emerging evidence links periprostatic adipose tissue (PPAT) inflammation, a consequence of metabolic impairment, and certain features of prostate cancer (PCa) aggressiveness. AT thromboinflammation, mediated by the proteolytic activation of protease‐activated receptors (PARs) particularly by thrombin and Factor Xa (FXa), drives AT dysfunction. Nevertheless, the contribution of PPAT thromboinflammation to early prostatic neoplastic alterations has not been investigated. Here, we utilized a non‐obese prediabetic rat model to assess prostatic neoplasia in association with PPAT thromboinflammation. Mild hypercaloric diet (MHC)‐fed rats exhibited hyperinsulinemia, hypertriglyceridemia, a lower metabolic efficiency, and a higher fat/lean ratio in comparison to regular chow‐fed rats. When compared to regular chow‐fed rats, MHC‐fed rats exhibited PPAT with larger adipocytes, enhanced oxidative stress and increased immune cell influx. Concurrently, prostates from MHC‐fed rats displayed highe...
Hybrid molecules targeting simultaneously DNA polymerase α (POLA1) and histone deacetylases (HDAC... more Hybrid molecules targeting simultaneously DNA polymerase α (POLA1) and histone deacetylases (HDACs) were designed and synthesized to exploit a potential synergy of action. Among a library of screened molecules, MIR002 and GEM144 showed antiproliferative activity at nanomolar concentrations on a panel of human solid and haematological cancer cell lines. In vitro functional assays confirmed that these molecules inhibited POLA1 primer extension activity, as well as HDAC11. Molecular docking studies also supported these findings. Mechanistically, MIR002 and GEM144 induced acetylation of p53, activation of p21, G1/S cell cycle arrest, and apoptosis. Oral administration of these inhibitors confirmed their antitumor activity in in vivo models. In human non-small cancer cell (H460) xenografted in nude mice MIR002 at 50 mg/kg, Bid (qd × 5 × 3w) inhibited tumor growth (TGI = 61%). More interestingly, in POLA1 inhibitor resistant cells (H460-R9A), the in vivo combination of MIR002 with cisplatin showed an additive antitumor effect with complete disappearance of tumor masses in two animals at the end of the treatment. Moreover, in two human orthotopic malignant pleural mesothelioma xenografts (MM473 and MM487), oral treatments with MIR002 and GEM144 confirmed their significant antitumor activity (TGI = 72-77%). Consistently with recent results that have shown an inverse correlation between POLA1 expression and type I interferon levels, MIR002 significantly upregulated interferon-α in immunocompetent mice.
ABSTRACTBackgroundVitamin A deficiency increases susceptibility to infection caused by impaired i... more ABSTRACTBackgroundVitamin A deficiency increases susceptibility to infection caused by impaired immune function.ObjectivesWe investigated whether immunodeficiency could facilitate the development of vitamin A deficiency.MethodsVitamin A deficiency was followed in 2 mouse models of immunodeficiency: the athymic nude mouse (nu/nu) and the humoral immunodeficient SENCAR (SENsitive to CARcinogenesis) mouse. Vitamin A deficiency was also monitored in outbred Balb/c and in NIH mice. The monitoring of vitamin A deficiency was done after feeding the mice and their mothers a semisynthetic, vitamin A–deficient diet from birth of the experimental mice. These mice were weaned onto the same deficient diet at 3–4 wk of age, while control groups were fed the same diet containing 3 μg retinoic acid per gram of diet.ResultsThe immunodeficient nu/nu and SENCAR mice developed vitamin A deficiency earlier than either the heterozygous nu/+ controls or the Balb/c and NIH strains. In female mice, symptoms...
To study the contribution of autocrine and paracrine TGF-beta 1 to tumor progression in a well-de... more To study the contribution of autocrine and paracrine TGF-beta 1 to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-beta 1 gene were initiated in vitro with the v-rasHa oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v-rasHa-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well-differentiated papillomas. Malignant progression was not associated with mutations in the c-rasHa gene, alterations in p53 protein, or loss of responsiveness to TGF-beta 1. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling ind...
Epigenetic mechanisms comprising DNA methylation, histone modifications, and noncoding RNAs affec... more Epigenetic mechanisms comprising DNA methylation, histone modifications, and noncoding RNAs affect chromatin structure and regulate gene expression. These mechanisms control normal embryonic development and adult life and their deregulation contributes to several diseases including cancer. The process of tumorigenesis is complex and results from the evolution of different "hallmarks of cancer". Hanahan and Weinberg presented in 2000 and 2011 seminal contributions in the cancer field, first the six hallmarks of cancer and a decade later two additional hallmarks and two enabling characteristics were added. Here, we surmise that epigenetic mechanisms regulate and contribute to every single hallmark in cancer, and thus represent the hallmark of hallmarks in tumorigenesis. Focusing on epigenetics as a major hallmark in cancer formation has profound preventive, therapeutic, and clinical implications.
Terpenoids are the largest class of natural products, most of which are derived from plants. Amon... more Terpenoids are the largest class of natural products, most of which are derived from plants. Amongst their numerous biological properties, their anti-tumor effects are of interest for they are extremely diverse which include anti-proliferative, apoptotic, anti-angiogenic, and anti-metastatic activities. Recently, several in vitro and in vivo studies have been dedicated to understanding the 'terpenoid induced autophagy' phenomenon in cancer cells. Light has already been shed on the intricacy of apoptosis and autophagy relationship. This latter crosstalk is driven by the delicate balance between activating or silencing of certain proteins whereby the outcome is expressed via interrelated signaling pathways. In this review, we focus on nine of the most studied terpenoids and on their cell death and autophagic activity. These terpenoids are grouped in three classes: sesquiterpenoid (artemisinin, parthenolide), diterpenoids (oridonin, triptolide), and triterpenoids (alisol, betulinic acid, oleanolic acid, platycodin D, and ursolic acid). We have selected these nine terpenoids among others as they belong to the different major classes of terpenoids and our extensive search of the literature indicated that they were the most studied in terms of autophagy in cancer. These terpenoids alone demonstrate the complexity by which these secondary metabolites induce autophagy via complex signaling pathways such as MAPK/ERK/JNK, PI3K/AKT/mTOR, AMPK, NF-kB, and reactive oxygen species. Moreover, induction of autophagy can be either destructive or protective in tumor cells. Nevertheless, should this phenomenon be well understood, we ought to be able to exploit it to create novel therapies and design more effective regimens in the management and treatment of cancer.
Background: Tumorigenesis is associated with deregulation of nutritional requirements, intermedia... more Background: Tumorigenesis is associated with deregulation of nutritional requirements, intermediary metabolites production, and microenvironment interactions. Unlike their normal cell counterparts, tumor cells rely on aerobic glycolysis, through the Warburg effect. Summary: The pentose phosphate pathway (PPP) is a major glucose metabolic shunt that is upregulated in cancer cells. The PPP comprises an oxidative and a nonoxidative phase and is essential for nucleotide synthesis of rapidly dividing cells. The PPP also generates nicotinamide adenine dinucleotide phosphate, which is required for reductive metabolism and to counteract oxidative stress in tumor cells. This article reviews the regulation of the PPP and discusses inhibitors that target its main pathways. Key Message: Exploiting the metabolic vulnerability of the PPP offers potential novel therapeutic opportunities and improves patients’ response to cancer therapy.
15 Regulation of Epithelial Differentiation by Retinoids Dean Rosenthal,* Francesca Lancillotti, ... more 15 Regulation of Epithelial Differentiation by Retinoids Dean Rosenthal,* Francesca Lancillotti, Nadine Darwiche, Rashmi Sinha, and Luigi M. De Luca National Cancer Institute, National Institutes of Health, Bethesda, Maryland I. INTRODUCTION Retinoids control ...
Acute myeloid leukemia (AML) is one of the most frequent, complex, and heterogeneous hematologica... more Acute myeloid leukemia (AML) is one of the most frequent, complex, and heterogeneous hematological malignancies. AML prognosis largely depends on acquired cytogenetic, epigenetic, and molecular abnormalities. Despite the improvement in understanding the biology of AML, survival rates remain quite low. Animal models offer a valuable tool to recapitulate different AML subtypes, and to assess the potential role of novel and known mutations in disease progression. This review provides a comprehensive and critical overview of select available AML animal models. These include the non-mammalian Zebrafish and Drosophila models as well as the mammalian rodent systems, comprising rats and mice. The suitability of each animal model, its contribution to the advancement of knowledge in AML pathophysiology and treatment, as well as its advantages and limitations are discussed. Despite some limitations, animal models represent a powerful approach to assess toxicity, and permit the design of new th...
Despite advances in therapeutic strategies, colorectal cancer (CRC) remains the third cause of ca... more Despite advances in therapeutic strategies, colorectal cancer (CRC) remains the third cause of cancer-related deaths with a relatively low survival rate. Resistance to standard chemotherapy represents a major hurdle in disease management; therefore, developing new therapeutic agents demands a thorough understanding of their mechanisms of action. One of these compounds is ST1926, an adamantyl retinoid that has shown potent antitumor activities in several human cancer models. Here, we show that ST1926 selectively suppressed the proliferation of CRC cells while sparing normal counterparts, and significantly reduced tumor volume in a xenograft cancer mouse model. Next, we investigated the effects of ST1926 in CRC cells and observed early DNA damage, S-phase arrest, dissipation of mitochondrial membrane potential, and apoptosis induction, in a p53 and p21-independent manner. To address the underlying mechanism of resistance to ST1926, we generated ST1926-resistant HCT116 cells and sequen...
The sesquiterpene lactone parthenolide is a major component of the feverfew medicinal plant, Tana... more The sesquiterpene lactone parthenolide is a major component of the feverfew medicinal plant, Tanacetum parthenium. Parthenolide has been extensively studied for its anti‐inflammatory and anticancer properties in several tumor models. Parthenolide's antitumor activities depend on several mechanisms but it is mainly known as an inhibitor of the nuclear factor‐κB (NF‐κB) pathway. This pathway is constitutively activated and induces cell survival in primary effusion lymphoma (PEL), a rare aggressive AIDS‐related lymphoproliferative disorder that is commonly caused by the human herpesvirus 8 (HHV‐8) infection. The aim of this study is to evaluate the targeted effect of Parthenolide both in vitro and in vivo. Herein, parthenolide significantly inhibited cell growth, induced G0/G1 cell cycle arrest, and induced massive apoptosis in PEL cells and ascites. In addition, parthenolide inhibited the NF‐ĸB pathway suppressing IĸB phosphorylation and p65 nuclear translocation. It also reduced ...
Ceramide (Cer) is a bioactive cellular lipid with compartmentalized and tightly regulated levels.... more Ceramide (Cer) is a bioactive cellular lipid with compartmentalized and tightly regulated levels. Distinct metabolic pathways lead to the generation of Cer species with distinguishable roles in oncogenesis. Deregulation of Cer pathways has emerged as an important mechanism for acquired chemotherapeutic resistance. Adult T-cell leukemia (ATL) cells are defective in Cer synthesis. ATL is an aggressive neoplasm that develops following infection with human T-cell lymphotropic virus-1 (HTLV-1) where the viral oncogene Tax contributes to the pathogenesis of the disease. ATL cells, resistant to all-trans-retinoic acid, are sensitive to pharmacologically achievable concentrations of the synthetic retinoid ST1926. We studied the effects of ST1926 on Cer pathways in ATL cells. ST1926 treatment resulted in early Tax oncoprotein degradation in HTLV-1-treated cells. ST1926 induced cell death and a dose- and time-dependent accumulation of Cer in malignant T cells. The kinetics and degree of Cer p...
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Papers by Nadine Darwiche