Current Medicinal Chemistry - Anti-inflammatory & Anti-allergy Agents, 2005
ABSTRACT This review describes our current understanding of telomere length polymorphism and orga... more ABSTRACT This review describes our current understanding of telomere length polymorphism and organization in breast cancer cells. The key roles of the telomeric DNA protein complexes as protectors of chromosomal ends in normal and cancer cells are under much attention in current research, and here we review some of these issues. In general the functionality of telomeres depends on a number of associated factors, like - (1) the length of the telomeric sequence at a particular chromosomal end, (2) the status of telomerase activity, (3) the telomere associated proteins, (4) the status of subtelomeric heterochromatinization, (5) or associated chromosomal instability. Specifically, in breast cancer, depending on the presence or absence of the mutations in DNA repair proteins the telomere function becomes much more fragile. Some recent studies using modern high performance three-dimensional (3D) imaging technologies indicate that many exciting aspects of this multifaceted telomere research are going to unfold further in the coming years.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 23, 2015
Persistent CD8 T cell expansion, low CD4/CD8 T cell ratios and heightened inflammation persist i... more Persistent CD8 T cell expansion, low CD4/CD8 T cell ratios and heightened inflammation persist in antiretroviral therapy (ART)-treated HIV infection and are associated with increased risk of morbid outcomes. We explored the role of cytomegalovirus (CMV) infection in CD8 lymphocytosis and inflammation in ART-treated HIV infection. Absolute CD4 and CD8 T cell counts were abstracted from clinical records and compared among 32 HIV-infected CMV-seronegative subjects, 126 age, CD4 and gender-matched HIV-infected CMV-seropositive subjects, and among 21 HIV-uninfected controls (9 CMV-, 12 CMV+). Plasma inflammatory indices were measured in a subset by ELISA. Median CD8 counts/μl were higher in HIV+CMV+ patients (795) than in HIV+CMV- subjects (522, p=0.006) or in healthy controls (451, p=0.0007) while CD8 T cell counts were similar to controls' levels in HIV+CMV- subjects. Higher plasma levels of IP-10 (P=0.0011), TNF-RII (P=0.0002), and D-dimer (P=0.0444) were also found in coinfect...
... Universitätsstraße 1, 40225 Düsseldorf, Ger-many Tumor Growth and Cell Proliferation MAREK LO... more ... Universitätsstraße 1, 40225 Düsseldorf, Ger-many Tumor Growth and Cell Proliferation MAREK LOS, Iran Rashedi, Soumya Panigrahi, Thomas Klonisch, and Klaus Schulze-Osthoff 2 Contents 2.1 Introduction: tumor Development and ...
Allogeneic immunocompetent splenocytes were tested for their ability to exert a GVT effect in a m... more Allogeneic immunocompetent splenocytes were tested for their ability to exert a GVT effect in a murine model of liver metastasis. Mammary carcinoma cells originating from an H-2(d) mouse were inoculated through the PV of F(1) (H-2(d/b)) mice, to mimic clinical hepatic involvement in malignant disease. Cell therapy was given either locally (PV) or systemically by IV inoculation to test differential efficacy of the GVT effect, and the differential expression of GVHD symptoms induced by diverse routes of administration. Livers of mice treated with H-2(b) derived splenocytes given PV or IV remained tumor-free for at least 4 weeks following tumor inoculation. Furthermore, all secondary recipients of adoptively transferred (AT) liver cells were tumor-free for >300 days. In contrast, all livers of untreated control mice or mice treated with syngeneic splenocytes displayed tumor metastases as early as 2 weeks following tumor inoculation, and large local tumors developed in AT secondary r...
Apoptin, a protein from the chicken anemia virus, has attracted attention because it specifically... more Apoptin, a protein from the chicken anemia virus, has attracted attention because it specifically kills tumor cells while leaving normal cells unharmed. The reason for this tumor selectivity is unclear and depends on subcellular localization, as apoptin resides in the cytoplasm of normal cells but in the nuclei of transformed cells. It was shown that nuclear localization and tumor-specific killing crucially require apoptin's phosphorylation by an as yet unknown kinase. Here we elucidate the pathway of apoptin-induced apoptosis and show that it essentially depends on abnormal phosphatidylinositol 3-kinase (PI3-kinase)/Akt activation, resulting in the activation of the cyclin-dependent kinase CDK2. Inhibitors as well as dominant-negative mutants of PI3-kinase and Akt not only inhibited CDK2 activation but also protected cells from apoptin-induced cell death. Akt activated CDK2 by direct phosphorylation as well as by the phosphorylation-induced degradation of the inhibitor p27(Kip1). Importantly, we also identified CDK2 as the principal kinase that phosphorylates apoptin and is crucially required for apoptin-induced cell death. Immortalized CDK2-deficient fibroblasts and CDK2 knockdown cells were markedly protected against apoptin. Thus, our results not only decipher the pathway of apoptin-induced cell death but also provide mechanistic insights for the selective killing of tumor cells.
Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeut... more Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and non-malignant diseases. Until recently, autologous and allogeneic bone marrow or mobilized blood stem cells transplantation were used primarily to replace malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimen were considered mandatory for more effective
Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imat... more Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxicity towards cancer cells, which can be directed towards inhibiting multiple hyperactive kinases including BCR-ABL1. Our earlier studies revealed that a proline-rich segment of apoptin interacts with the SH3 domain of fusion protein BCR-ABL1 (p210) and acts as a negative regulator of BCR-ABL1 kinase and its downstream targets. In this study we show for the first time, the therapeutic potential of apoptin-derived decapeptide for the treatment of CML by establishing the minimal region of apoptin interaction domain with BCR-ABL1. We further show that the apoptin decapeptide is able to inhibit BCR-ABL1 down stream target c-Myc with a comparable efficacy to full-length apoptin and Imatinib. The...
Increased risk of delayed hemolysis following conventional minor ABO mismatched allogeneic bone m... more Increased risk of delayed hemolysis following conventional minor ABO mismatched allogeneic bone marrow transplantation (BMT) has been found to be associated with peripheral blood stem cell transplantation (PBSCT), non-T-cell depletion, and immunosuppression by Cyclosporin A (CSA) or FK506. We recently demonstrated that it is possible to achieve stable engraftment with mixed or complete chimerism using nonmyeloablative conditioning consisting of Fludarabine,
The partial cross-utilization of molecules and pathways involved in opposing processes like cell ... more The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16(Ink4a), p15(Ink4b), p18(Ink4c), p19(Ink4d)), and the Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X(L) Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X(S); Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G1-S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.
Current Medicinal Chemistry - Anti-inflammatory & Anti-allergy Agents, 2005
ABSTRACT This review describes our current understanding of telomere length polymorphism and orga... more ABSTRACT This review describes our current understanding of telomere length polymorphism and organization in breast cancer cells. The key roles of the telomeric DNA protein complexes as protectors of chromosomal ends in normal and cancer cells are under much attention in current research, and here we review some of these issues. In general the functionality of telomeres depends on a number of associated factors, like - (1) the length of the telomeric sequence at a particular chromosomal end, (2) the status of telomerase activity, (3) the telomere associated proteins, (4) the status of subtelomeric heterochromatinization, (5) or associated chromosomal instability. Specifically, in breast cancer, depending on the presence or absence of the mutations in DNA repair proteins the telomere function becomes much more fragile. Some recent studies using modern high performance three-dimensional (3D) imaging technologies indicate that many exciting aspects of this multifaceted telomere research are going to unfold further in the coming years.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 23, 2015
Persistent CD8 T cell expansion, low CD4/CD8 T cell ratios and heightened inflammation persist i... more Persistent CD8 T cell expansion, low CD4/CD8 T cell ratios and heightened inflammation persist in antiretroviral therapy (ART)-treated HIV infection and are associated with increased risk of morbid outcomes. We explored the role of cytomegalovirus (CMV) infection in CD8 lymphocytosis and inflammation in ART-treated HIV infection. Absolute CD4 and CD8 T cell counts were abstracted from clinical records and compared among 32 HIV-infected CMV-seronegative subjects, 126 age, CD4 and gender-matched HIV-infected CMV-seropositive subjects, and among 21 HIV-uninfected controls (9 CMV-, 12 CMV+). Plasma inflammatory indices were measured in a subset by ELISA. Median CD8 counts/μl were higher in HIV+CMV+ patients (795) than in HIV+CMV- subjects (522, p=0.006) or in healthy controls (451, p=0.0007) while CD8 T cell counts were similar to controls' levels in HIV+CMV- subjects. Higher plasma levels of IP-10 (P=0.0011), TNF-RII (P=0.0002), and D-dimer (P=0.0444) were also found in coinfect...
... Universitätsstraße 1, 40225 Düsseldorf, Ger-many Tumor Growth and Cell Proliferation MAREK LO... more ... Universitätsstraße 1, 40225 Düsseldorf, Ger-many Tumor Growth and Cell Proliferation MAREK LOS, Iran Rashedi, Soumya Panigrahi, Thomas Klonisch, and Klaus Schulze-Osthoff 2 Contents 2.1 Introduction: tumor Development and ...
Allogeneic immunocompetent splenocytes were tested for their ability to exert a GVT effect in a m... more Allogeneic immunocompetent splenocytes were tested for their ability to exert a GVT effect in a murine model of liver metastasis. Mammary carcinoma cells originating from an H-2(d) mouse were inoculated through the PV of F(1) (H-2(d/b)) mice, to mimic clinical hepatic involvement in malignant disease. Cell therapy was given either locally (PV) or systemically by IV inoculation to test differential efficacy of the GVT effect, and the differential expression of GVHD symptoms induced by diverse routes of administration. Livers of mice treated with H-2(b) derived splenocytes given PV or IV remained tumor-free for at least 4 weeks following tumor inoculation. Furthermore, all secondary recipients of adoptively transferred (AT) liver cells were tumor-free for >300 days. In contrast, all livers of untreated control mice or mice treated with syngeneic splenocytes displayed tumor metastases as early as 2 weeks following tumor inoculation, and large local tumors developed in AT secondary r...
Apoptin, a protein from the chicken anemia virus, has attracted attention because it specifically... more Apoptin, a protein from the chicken anemia virus, has attracted attention because it specifically kills tumor cells while leaving normal cells unharmed. The reason for this tumor selectivity is unclear and depends on subcellular localization, as apoptin resides in the cytoplasm of normal cells but in the nuclei of transformed cells. It was shown that nuclear localization and tumor-specific killing crucially require apoptin's phosphorylation by an as yet unknown kinase. Here we elucidate the pathway of apoptin-induced apoptosis and show that it essentially depends on abnormal phosphatidylinositol 3-kinase (PI3-kinase)/Akt activation, resulting in the activation of the cyclin-dependent kinase CDK2. Inhibitors as well as dominant-negative mutants of PI3-kinase and Akt not only inhibited CDK2 activation but also protected cells from apoptin-induced cell death. Akt activated CDK2 by direct phosphorylation as well as by the phosphorylation-induced degradation of the inhibitor p27(Kip1). Importantly, we also identified CDK2 as the principal kinase that phosphorylates apoptin and is crucially required for apoptin-induced cell death. Immortalized CDK2-deficient fibroblasts and CDK2 knockdown cells were markedly protected against apoptin. Thus, our results not only decipher the pathway of apoptin-induced cell death but also provide mechanistic insights for the selective killing of tumor cells.
Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeut... more Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and non-malignant diseases. Until recently, autologous and allogeneic bone marrow or mobilized blood stem cells transplantation were used primarily to replace malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimen were considered mandatory for more effective
Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imat... more Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxicity towards cancer cells, which can be directed towards inhibiting multiple hyperactive kinases including BCR-ABL1. Our earlier studies revealed that a proline-rich segment of apoptin interacts with the SH3 domain of fusion protein BCR-ABL1 (p210) and acts as a negative regulator of BCR-ABL1 kinase and its downstream targets. In this study we show for the first time, the therapeutic potential of apoptin-derived decapeptide for the treatment of CML by establishing the minimal region of apoptin interaction domain with BCR-ABL1. We further show that the apoptin decapeptide is able to inhibit BCR-ABL1 down stream target c-Myc with a comparable efficacy to full-length apoptin and Imatinib. The...
Increased risk of delayed hemolysis following conventional minor ABO mismatched allogeneic bone m... more Increased risk of delayed hemolysis following conventional minor ABO mismatched allogeneic bone marrow transplantation (BMT) has been found to be associated with peripheral blood stem cell transplantation (PBSCT), non-T-cell depletion, and immunosuppression by Cyclosporin A (CSA) or FK506. We recently demonstrated that it is possible to achieve stable engraftment with mixed or complete chimerism using nonmyeloablative conditioning consisting of Fludarabine,
The partial cross-utilization of molecules and pathways involved in opposing processes like cell ... more The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16(Ink4a), p15(Ink4b), p18(Ink4c), p19(Ink4d)), and the Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X(L) Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X(S); Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G1-S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.
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Papers by Soumya Panigrahi