The study of pharmacokinetics (PK) and pharmacodynamics (PD) in cancer drug discovery and develop... more The study of pharmacokinetics (PK) and pharmacodynamics (PD) in cancer drug discovery and development is often paired and described in reciprocal terms, where PK is the analysis of the change in drug concentration with time and PD is the analysis of the biological effects of the drug at various concentrations over different time courses. While PK is defined by how a compound is absorbed, distributed, metabolized, and eliminated, PD refers to the measure of a compound's ability to interact with its intended target, leading to a biologic effect. Recent advances in anti-breast cancer drug discovery have resulted in several new drugs, but there is still a high attrition rate during clinical development. One reason for this failure is attributed to inappropriate correlation between the PK and PD parameters and subsequent extrapolation to human subjects. In this chapter, we describe the protocols of PK and PD studies in breast cancer models to assess the efficacy of an anti-breast cancer compound, noting the types and endpoints employed, and explain why it is important to link PK and PD in order to establish and evaluate dose/concentration-response relationships and subsequently describe and predict the effect-time courses for a given drug dose.
The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progres... more The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the efficiency of MDM2 targeting, anticancer efficacy, pharmacokinetics, and safety were evaluated in in vitro and in vivo models of human prostate cancer. Our results indicated that, compared with the unencapsulated GS25, GS25NP demonstrated better MDM2 inhibition, improved oral bioavailability and enhanced in vitro and in vivo activities. In conclusion, the validated nano-formulation for GS25 oral delivery improves its molecular targeting, oral bioavailability and anticancer efficacy, providing a basis for further development of GS25 as a novel agent for cancer therapy and prevention.
RYBP is a member of the polycomb group (PcG) proteins that typically act as transcriptional repre... more RYBP is a member of the polycomb group (PcG) proteins that typically act as transcriptional repressors via epigenetic modification of chromatin. The present study was designed to investigate the role of RYBP in HCC progression, chemosensitivity, and patient survival, and to explore the underlying molecular mechanism(s). In this study we investigated the expression of RYBP in 400 pairs of human HCC tissues and matched noncancerous samples. The effects of RYBP on HCC tumor growth and metastasis and chemosensitivity were determined both in vitro and in vivo. We herein demonstrate that the RYBP expression in HCC tissue samples was signiï¬cantly lower than that in matched noncancerous liver tissues. Clinically, the low expression of RYBP was an independent predictor of a poor prognosis in patients with HCC. In in vitro HCC models, enforced RYBP expression inhibited cell growth and invasion, induced apoptosis, and increased the chemosensitivity of the cells, while RYBP knockdown led to the opposite effects. Furthermore, RYBP expression was induced by cisplatin, and adenovirus-mediated RYBP expression inhibited HCC tumor growth and sensitized HCC to conventional chemotherapy in vivo. Our results demonstrate that reactivating RYBP in cancer cells may provide an effective and safe therapeutic approach to HCC therapy.
We have recently designed and synthesized several novel iminoquinone anticancer agents that have ... more We have recently designed and synthesized several novel iminoquinone anticancer agents that have entered preclinical development for the treatment of human cancers. Herein we developed and validated a quantitative HPLC-MS/MS analytical method for one of the lead novel anticancer makaluvamine analog, TCBA-TPQ, and conducted a pharmacokinetic study in laboratory rats. Our results indicated that the HPLC-MS/MS method was precise, accurate, and specific. Using this method, we carried out in vitro and in vivo evaluations of the pharmacological properties of TCBA-TPQ and plasma pharmacokinetics in rats. Our results provide a basis for future preclinical and clinical development of this promising anticancer marine analog.
Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial develo... more Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial developmental and physiological processes in the cell. More recently, they have been found to play important roles in human carcinogenesis and cancer development and progression. The deregulation and dysfunction of PcG proteins often lead to blocking or inappropriate activation of developmental pathways, enhancing cellular proliferation, inhibiting apoptosis, and increasing the cancer stem cell population. Genetic and molecular investigations of PcG proteins have long been focused on their PcG functions. However, PcG proteins have recently been shown to exert non-classical-Pc-functions, contributing to the regulation of diverse cellular functions. We and others have demonstrated that PcG proteins regulate the expression and function of several oncogenes and tumor suppressor genes in a PcG-independent manner, and PcG proteins are associated with the survival of patients with cancer. In this rev...
The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progres... more The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the efficiency of MDM2 targeting, anticancer efficacy, pharmacokinetics, and safety were evaluated in in vitro an...
RYBP is a member of the polycomb group (PcG) proteins that typically act as transcriptional repre... more RYBP is a member of the polycomb group (PcG) proteins that typically act as transcriptional repressors via epigenetic modification of chromatin. The present study was designed to investigate the role of RYBP in HCC progression, chemosensitivity, and patient survival, and to explore the underlying molecular mechanism(s). In this study we investigated the expression of RYBP in 400 pairs of human HCC tissues and matched noncancerous samples. The effects of RYBP on HCC tumor growth and metastasis and chemosensitivity were determined both in vitro and in vivo. We herein demonstrate that the RYBP expression in HCC tissue samples was signiï¬cantly lower than that in matched noncancerous liver tissues. Clinically, the low expression of RYBP was an independent predictor of a poor prognosis in patients with HCC. In in vitro HCC models, enforced RYBP expression inhibited cell growth and invasion, induced apoptosis, and increased the chemosensitivity of the cells, while RYBP knockdown led to t...
Thiazolidinedione (TZD) compounds have shown promise as antidiabetic, antibiotics, antifungal and... more Thiazolidinedione (TZD) compounds have shown promise as antidiabetic, antibiotics, antifungal and neuroprotective agents. The mitochondrial effect of a novel mitoNEET ligand, NL-1 {5-[(3,5-di-tert-butyl-4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione}, and other TZD compounds, is a newly proposed mechanism for the neuroprotective action of these TZD compounds. In this work, a sensitive LC-MS/MS assay has been developed and validated for quantification of NL-1 in mouse serum. Sample preparation involved an acetonitrile protein precipitation procedure with addition of an internal standard NL-2 {5-[(4-hydroxy-3,5-dimethyl-phenyl)methyl]thiazolidine-2,4-dione}. LC-MS/MS analysis utilized a Columbus C-18 HPLC column (2mm×50mm, 5μm). Chromatography employed a multiple step gradient program that featured a steep linear gradient (25-95% in 0.5min) of 15μM ammonium acetate (additive for eliminating carry-over) in 2% methanol mixing with increasing proportions of 100% methanol. The HPLC was interfaced to a QTrap 5500 mass spectrometer (AB Sciex) equipped with an electrospray ionization source used in a negative ionization mode. Multiple reaction monitoring (MRM) of m/z 334→263 for NL-1 and m/z 250→179 for NL-2 was done. The method had a linear range of at least 1-100ng/mL in serum. The intra-assay and inter-assay percent coefficient of variation (%CV) were less than 4% and accuracies (%RE) ranged from -2.7% to 2.0%. The analytical procedure gave 96-115% absolute extraction recovery of NL-1. The relative matrix effect was measured and found to be insignificant. The analyte in serum was confirmed to be stable during storage and treatment. The method is suitable for pharmacokinetic (PK) studies of the parent drug NL-1 based on the preliminary serum results from dosed NL-1 mouse studies.
ABSTRACT The marine ecosystem presents an immensely rich chemical and biological resource for the... more ABSTRACT The marine ecosystem presents an immensely rich chemical and biological resource for the discovery of new anticancer drugs. Recently, marine alkaloids, isolated from various aquatic flora and fauna, have been found to exhibit potent anticancer activities. These compounds range structurally from simple linear peptides to complex macrocyclic polyethers and are amenable to synthetic derivatization. Makaluvamines, a class of iminoquinone alkaloids isolated from marine sponges of the genera Zyzzya, have been reported to possess excellent in vitro and in vivo cytotoxicity against several cancer types. Until recently, these compounds have been thought to mainly act as DNA topoisomerase II inhibitors. A series of synthetic makaluvamine analogs have now been shown to inhibit cell proliferation and cell cycle progression, to induce apoptosis, and to modulate the expression of several genes such as MDM2, p21, and p53. The in vitro and in vivo results reported thus far provide a basis for future preclinical and clinical development of this class of compounds for cancer therapy.
The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA r... more The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.
Thiazolidinedione (TZD) compounds have shown promise as antidiabetic, antibiotics, antifungal and... more Thiazolidinedione (TZD) compounds have shown promise as antidiabetic, antibiotics, antifungal and neuroprotective agents. The mitochondrial effect of a novel mitoNEET ligand, NL-1 {5-[(3,5-di-tert-butyl-4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione}, and other TZD compounds, is a newly proposed mechanism for the neuroprotective action of these TZD compounds. In this work, a sensitive LC-MS/MS assay has been developed and validated for quantification of NL-1 in mouse serum. Sample preparation involved an acetonitrile protein precipitation procedure with addition of an internal standard NL-2 {5-[(4-hydroxy-3,5-dimethyl-phenyl)methyl]thiazolidine-2,4-dione}. LC-MS/MS analysis utilized a Columbus C-18 HPLC column (2mm×50mm, 5μm). Chromatography employed a multiple step gradient program that featured a steep linear gradient (25-95% in 0.5min) of 15μM ammonium acetate (additive for eliminating carry-over) in 2% methanol mixing with increasing proportions of 100% methanol. The HPLC was interfaced to a QTrap 5500 mass spectrometer (AB Sciex) equipped with an electrospray ionization source used in a negative ionization mode. Multiple reaction monitoring (MRM) of m/z 334→263 for NL-1 and m/z 250→179 for NL-2 was done. The method had a linear range of at least 1-100ng/mL in serum. The intra-assay and inter-assay percent coefficient of variation (%CV) were less than 4% and accuracies (%RE) ranged from -2.7% to 2.0%. The analytical procedure gave 96-115% absolute extraction recovery of NL-1. The relative matrix effect was measured and found to be insignificant. The analyte in serum was confirmed to be stable during storage and treatment. The method is suitable for pharmacokinetic (PK) studies of the parent drug NL-1 based on the preliminary serum results from dosed NL-1 mouse studies.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2014
The NFAT signaling pathway regulates various aspects of cellular functions; NFAT acts as a calciu... more The NFAT signaling pathway regulates various aspects of cellular functions; NFAT acts as a calcium sensor, integrating calcium signaling with other pathways involved in development and growth, immune response, and inflammatory response. The NFAT family of transcription factors regulates diverse cellular functions such as cell survival, proliferation, migration, invasion, and angiogenesis. The NFAT isoforms are constitutively activated and overexpressed in several cancer types wherein they transactivate downstream targets that play important roles in cancer development and progression. Though the NFAT family has been conclusively proved to be pivotal in cancer progression, the different isoforms play distinct roles in different cellular contexts. In this review, our discussion is focused on the mechanisms that drive the activation of various NFAT isoforms in cancer. Additionally, we analyze the potential of NFAT as a valid target for cancer prevention and therapy.
Ribosomes are essential components of the protein synthesis machinery. The process of ribosome bi... more Ribosomes are essential components of the protein synthesis machinery. The process of ribosome biogenesis is well organized and tightly regulated. Recent studies have shown that ribosomal proteins (RPs) have extraribosomal functions that are involved in cell proliferation, differentiation, apoptosis, DNA repair, and other cellular processes. The dysfunction of RPs has been linked to the development and progression of hematological, metabolic, and cardiovascular diseases and cancer. Perturbation of ribosome biogenesis results in ribosomal stress, which triggers activation of the p53 signaling pathway through RPs-MDM2 interactions, resulting in p53-dependent cell cycle arrest and apoptosis. RPs also regulate cellular functions through p53-independent mechanisms. We herein review the recent advances in several forefronts of RP research, including the understanding of their biological features and roles in regulating cellular functions, maintaining cell homeostasis, and their involvement in the pathogenesis of human diseases. We also highlight the translational potential of this research for the identification of molecular biomarkers, and in the discovery and development of novel treatments for human diseases.
The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a comm... more The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.
The study of pharmacokinetics (PK) and pharmacodynamics (PD) in cancer drug discovery and develop... more The study of pharmacokinetics (PK) and pharmacodynamics (PD) in cancer drug discovery and development is often paired and described in reciprocal terms, where PK is the analysis of the change in drug concentration with time and PD is the analysis of the biological effects of the drug at various concentrations over different time courses. While PK is defined by how a compound is absorbed, distributed, metabolized, and eliminated, PD refers to the measure of a compound's ability to interact with its intended target, leading to a biologic effect. Recent advances in anti-breast cancer drug discovery have resulted in several new drugs, but there is still a high attrition rate during clinical development. One reason for this failure is attributed to inappropriate correlation between the PK and PD parameters and subsequent extrapolation to human subjects. In this chapter, we describe the protocols of PK and PD studies in breast cancer models to assess the efficacy of an anti-breast cancer compound, noting the types and endpoints employed, and explain why it is important to link PK and PD in order to establish and evaluate dose/concentration-response relationships and subsequently describe and predict the effect-time courses for a given drug dose.
The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progres... more The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the efficiency of MDM2 targeting, anticancer efficacy, pharmacokinetics, and safety were evaluated in in vitro and in vivo models of human prostate cancer. Our results indicated that, compared with the unencapsulated GS25, GS25NP demonstrated better MDM2 inhibition, improved oral bioavailability and enhanced in vitro and in vivo activities. In conclusion, the validated nano-formulation for GS25 oral delivery improves its molecular targeting, oral bioavailability and anticancer efficacy, providing a basis for further development of GS25 as a novel agent for cancer therapy and prevention.
RYBP is a member of the polycomb group (PcG) proteins that typically act as transcriptional repre... more RYBP is a member of the polycomb group (PcG) proteins that typically act as transcriptional repressors via epigenetic modification of chromatin. The present study was designed to investigate the role of RYBP in HCC progression, chemosensitivity, and patient survival, and to explore the underlying molecular mechanism(s). In this study we investigated the expression of RYBP in 400 pairs of human HCC tissues and matched noncancerous samples. The effects of RYBP on HCC tumor growth and metastasis and chemosensitivity were determined both in vitro and in vivo. We herein demonstrate that the RYBP expression in HCC tissue samples was signiï¬cantly lower than that in matched noncancerous liver tissues. Clinically, the low expression of RYBP was an independent predictor of a poor prognosis in patients with HCC. In in vitro HCC models, enforced RYBP expression inhibited cell growth and invasion, induced apoptosis, and increased the chemosensitivity of the cells, while RYBP knockdown led to the opposite effects. Furthermore, RYBP expression was induced by cisplatin, and adenovirus-mediated RYBP expression inhibited HCC tumor growth and sensitized HCC to conventional chemotherapy in vivo. Our results demonstrate that reactivating RYBP in cancer cells may provide an effective and safe therapeutic approach to HCC therapy.
We have recently designed and synthesized several novel iminoquinone anticancer agents that have ... more We have recently designed and synthesized several novel iminoquinone anticancer agents that have entered preclinical development for the treatment of human cancers. Herein we developed and validated a quantitative HPLC-MS/MS analytical method for one of the lead novel anticancer makaluvamine analog, TCBA-TPQ, and conducted a pharmacokinetic study in laboratory rats. Our results indicated that the HPLC-MS/MS method was precise, accurate, and specific. Using this method, we carried out in vitro and in vivo evaluations of the pharmacological properties of TCBA-TPQ and plasma pharmacokinetics in rats. Our results provide a basis for future preclinical and clinical development of this promising anticancer marine analog.
Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial develo... more Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial developmental and physiological processes in the cell. More recently, they have been found to play important roles in human carcinogenesis and cancer development and progression. The deregulation and dysfunction of PcG proteins often lead to blocking or inappropriate activation of developmental pathways, enhancing cellular proliferation, inhibiting apoptosis, and increasing the cancer stem cell population. Genetic and molecular investigations of PcG proteins have long been focused on their PcG functions. However, PcG proteins have recently been shown to exert non-classical-Pc-functions, contributing to the regulation of diverse cellular functions. We and others have demonstrated that PcG proteins regulate the expression and function of several oncogenes and tumor suppressor genes in a PcG-independent manner, and PcG proteins are associated with the survival of patients with cancer. In this rev...
The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progres... more The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the efficiency of MDM2 targeting, anticancer efficacy, pharmacokinetics, and safety were evaluated in in vitro an...
RYBP is a member of the polycomb group (PcG) proteins that typically act as transcriptional repre... more RYBP is a member of the polycomb group (PcG) proteins that typically act as transcriptional repressors via epigenetic modification of chromatin. The present study was designed to investigate the role of RYBP in HCC progression, chemosensitivity, and patient survival, and to explore the underlying molecular mechanism(s). In this study we investigated the expression of RYBP in 400 pairs of human HCC tissues and matched noncancerous samples. The effects of RYBP on HCC tumor growth and metastasis and chemosensitivity were determined both in vitro and in vivo. We herein demonstrate that the RYBP expression in HCC tissue samples was signiï¬cantly lower than that in matched noncancerous liver tissues. Clinically, the low expression of RYBP was an independent predictor of a poor prognosis in patients with HCC. In in vitro HCC models, enforced RYBP expression inhibited cell growth and invasion, induced apoptosis, and increased the chemosensitivity of the cells, while RYBP knockdown led to t...
Thiazolidinedione (TZD) compounds have shown promise as antidiabetic, antibiotics, antifungal and... more Thiazolidinedione (TZD) compounds have shown promise as antidiabetic, antibiotics, antifungal and neuroprotective agents. The mitochondrial effect of a novel mitoNEET ligand, NL-1 {5-[(3,5-di-tert-butyl-4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione}, and other TZD compounds, is a newly proposed mechanism for the neuroprotective action of these TZD compounds. In this work, a sensitive LC-MS/MS assay has been developed and validated for quantification of NL-1 in mouse serum. Sample preparation involved an acetonitrile protein precipitation procedure with addition of an internal standard NL-2 {5-[(4-hydroxy-3,5-dimethyl-phenyl)methyl]thiazolidine-2,4-dione}. LC-MS/MS analysis utilized a Columbus C-18 HPLC column (2mm×50mm, 5μm). Chromatography employed a multiple step gradient program that featured a steep linear gradient (25-95% in 0.5min) of 15μM ammonium acetate (additive for eliminating carry-over) in 2% methanol mixing with increasing proportions of 100% methanol. The HPLC was interfaced to a QTrap 5500 mass spectrometer (AB Sciex) equipped with an electrospray ionization source used in a negative ionization mode. Multiple reaction monitoring (MRM) of m/z 334→263 for NL-1 and m/z 250→179 for NL-2 was done. The method had a linear range of at least 1-100ng/mL in serum. The intra-assay and inter-assay percent coefficient of variation (%CV) were less than 4% and accuracies (%RE) ranged from -2.7% to 2.0%. The analytical procedure gave 96-115% absolute extraction recovery of NL-1. The relative matrix effect was measured and found to be insignificant. The analyte in serum was confirmed to be stable during storage and treatment. The method is suitable for pharmacokinetic (PK) studies of the parent drug NL-1 based on the preliminary serum results from dosed NL-1 mouse studies.
ABSTRACT The marine ecosystem presents an immensely rich chemical and biological resource for the... more ABSTRACT The marine ecosystem presents an immensely rich chemical and biological resource for the discovery of new anticancer drugs. Recently, marine alkaloids, isolated from various aquatic flora and fauna, have been found to exhibit potent anticancer activities. These compounds range structurally from simple linear peptides to complex macrocyclic polyethers and are amenable to synthetic derivatization. Makaluvamines, a class of iminoquinone alkaloids isolated from marine sponges of the genera Zyzzya, have been reported to possess excellent in vitro and in vivo cytotoxicity against several cancer types. Until recently, these compounds have been thought to mainly act as DNA topoisomerase II inhibitors. A series of synthetic makaluvamine analogs have now been shown to inhibit cell proliferation and cell cycle progression, to induce apoptosis, and to modulate the expression of several genes such as MDM2, p21, and p53. The in vitro and in vivo results reported thus far provide a basis for future preclinical and clinical development of this class of compounds for cancer therapy.
The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA r... more The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.
Thiazolidinedione (TZD) compounds have shown promise as antidiabetic, antibiotics, antifungal and... more Thiazolidinedione (TZD) compounds have shown promise as antidiabetic, antibiotics, antifungal and neuroprotective agents. The mitochondrial effect of a novel mitoNEET ligand, NL-1 {5-[(3,5-di-tert-butyl-4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione}, and other TZD compounds, is a newly proposed mechanism for the neuroprotective action of these TZD compounds. In this work, a sensitive LC-MS/MS assay has been developed and validated for quantification of NL-1 in mouse serum. Sample preparation involved an acetonitrile protein precipitation procedure with addition of an internal standard NL-2 {5-[(4-hydroxy-3,5-dimethyl-phenyl)methyl]thiazolidine-2,4-dione}. LC-MS/MS analysis utilized a Columbus C-18 HPLC column (2mm×50mm, 5μm). Chromatography employed a multiple step gradient program that featured a steep linear gradient (25-95% in 0.5min) of 15μM ammonium acetate (additive for eliminating carry-over) in 2% methanol mixing with increasing proportions of 100% methanol. The HPLC was interfaced to a QTrap 5500 mass spectrometer (AB Sciex) equipped with an electrospray ionization source used in a negative ionization mode. Multiple reaction monitoring (MRM) of m/z 334→263 for NL-1 and m/z 250→179 for NL-2 was done. The method had a linear range of at least 1-100ng/mL in serum. The intra-assay and inter-assay percent coefficient of variation (%CV) were less than 4% and accuracies (%RE) ranged from -2.7% to 2.0%. The analytical procedure gave 96-115% absolute extraction recovery of NL-1. The relative matrix effect was measured and found to be insignificant. The analyte in serum was confirmed to be stable during storage and treatment. The method is suitable for pharmacokinetic (PK) studies of the parent drug NL-1 based on the preliminary serum results from dosed NL-1 mouse studies.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2014
The NFAT signaling pathway regulates various aspects of cellular functions; NFAT acts as a calciu... more The NFAT signaling pathway regulates various aspects of cellular functions; NFAT acts as a calcium sensor, integrating calcium signaling with other pathways involved in development and growth, immune response, and inflammatory response. The NFAT family of transcription factors regulates diverse cellular functions such as cell survival, proliferation, migration, invasion, and angiogenesis. The NFAT isoforms are constitutively activated and overexpressed in several cancer types wherein they transactivate downstream targets that play important roles in cancer development and progression. Though the NFAT family has been conclusively proved to be pivotal in cancer progression, the different isoforms play distinct roles in different cellular contexts. In this review, our discussion is focused on the mechanisms that drive the activation of various NFAT isoforms in cancer. Additionally, we analyze the potential of NFAT as a valid target for cancer prevention and therapy.
Ribosomes are essential components of the protein synthesis machinery. The process of ribosome bi... more Ribosomes are essential components of the protein synthesis machinery. The process of ribosome biogenesis is well organized and tightly regulated. Recent studies have shown that ribosomal proteins (RPs) have extraribosomal functions that are involved in cell proliferation, differentiation, apoptosis, DNA repair, and other cellular processes. The dysfunction of RPs has been linked to the development and progression of hematological, metabolic, and cardiovascular diseases and cancer. Perturbation of ribosome biogenesis results in ribosomal stress, which triggers activation of the p53 signaling pathway through RPs-MDM2 interactions, resulting in p53-dependent cell cycle arrest and apoptosis. RPs also regulate cellular functions through p53-independent mechanisms. We herein review the recent advances in several forefronts of RP research, including the understanding of their biological features and roles in regulating cellular functions, maintaining cell homeostasis, and their involvement in the pathogenesis of human diseases. We also highlight the translational potential of this research for the identification of molecular biomarkers, and in the discovery and development of novel treatments for human diseases.
The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a comm... more The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.
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Papers by Subhasree Nag