Nicotine: Could it alleviate the mortality of viral hemorrhagic fevers such as Ebola by reducing endothelial inflammation?
The majority of studies regarding nicotine have focused on the detrimental effects of nicotine in a plethora of physiopathological processes. However, recent studies have appreciated some beneficial effects of nicotine in various conditions. For instance, nicotine reduces the activity of aromatase involved in estrogen biosynthesis, which is a growth-inducing hormone for breast, ovarium and endometrial cancer. However, since smoking fume contains numerous carcinogens, it can not be concluded that smoking is beneficial in estrogen-dependent cancers. Nonetheless, transdermal nicotine or nicotine gums may exert some benefits and experimental studies demonstrated reduction of breast cancer growth with nicotine in animal models. Furthermore, nicotine exerts anxiolytic, anti-depressive and anti-obsessive effects in psychiatrical conditions.
Therefore, some have commented that high rates of smoking in bipolar disorder patients (and very high rates in schizophrenics) may be a self-medication mechanism to reduce the disease burden. Since inflammation is more and more recognized as an important contributing factor to psychiatric diseases, nicotine's psychiatric effects may also be explained by its anti-inflammatory actions. Additionally, enhancing evidence indicates positive effects of nicotine in ameliorating Alzheimer's Disease.
Nicotine also modifies the inflammatory stage of endothelial cells. While some studies showed negative effects of nicotine on endothelial function and integrity, there exist also a mounting evidence regarding nicotine alleviation of endothelial inflammation. Very interestingly, there also exist clinical data suggesting nicotine suppression of Kaposi Sarcoma, which is a malignancy origined from endothelial cells. It is known that chronic inflammation contributes to the growth of malignancies by stimulating angiogenesis and immunosuppression. Thus, this fact is parallel to the observations demonstrating nicotine reduction of endothelial inflammation. Moreover, pure nicotine increases PAI-1 (Plasminogen Activator Inhibitor-1) synthesis. Here, I propose that it would be worthwhile to test nicotine in treatment of viral hemorrhagic fevers.
Wednesday, October 29, 2014
EBOLA, folate receptor-1, farletuzumab and cancer
EBOLA, a virus disease causing a global health alarm and one of the most fatal type of viral hemorrhagic fevers employs folate receptor-1 for cellular entry. Folate receptor-1/FLR-1 is also one of the important proteins upregulated in cancer facilitating enhanced folate entry, which is used for nucleotide synthesis to maintain increased DNA synthesis. Currently, FLR-1 inhibitor farletuzumab is tested in Phase-3 trials for the treatment of ovarian cancer. This agent may also act beneficial in blocking EBOLA entry into cells and help alleviating the severity of EBOLA. Vice versa, if medicine could modify the deadly course of this virus disease by modifying the viral genotype in future, EBOLA virus may act as a gene therapy vector similar to the current approaches to employ modified AIDS virus and other members of lentiviridae in gene delivery.
EBOLA, a virus disease causing a global health alarm and one of the most fatal type of viral hemorrhagic fevers employs folate receptor-1 for cellular entry. Folate receptor-1/FLR-1 is also one of the important proteins upregulated in cancer facilitating enhanced folate entry, which is used for nucleotide synthesis to maintain increased DNA synthesis. Currently, FLR-1 inhibitor farletuzumab is tested in Phase-3 trials for the treatment of ovarian cancer. This agent may also act beneficial in blocking EBOLA entry into cells and help alleviating the severity of EBOLA. Vice versa, if medicine could modify the deadly course of this virus disease by modifying the viral genotype in future, EBOLA virus may act as a gene therapy vector similar to the current approaches to employ modified AIDS virus and other members of lentiviridae in gene delivery.
Neuroblastoma, ALK, PI3-Kinase and mTOR pathways: Tumor's embryonic mimicry and new hopes for the management of neuroblastoma with tyrosine kinase inhibitor - immunestimulant cocktails
Neuroblastoma, the most common extracranial solid cancer in childhood and the most common cancer in infancy can exert a grave course. CD246/ALK (Anaplastic Lymphoma Kinase) is an important protein in neurodevelopment and one of the most important therapeutic targets in neuroblastoma biogenesis. Since the discovery of the oncofetal antigens in 1970's, it is well established that tumors reactivate embryonic genes for growth, invasion, angiogenesis and escape from immuno-surveillance. Crizotinib (Xalkori(R), Pfizer) the aminopyrimine type inhibitor of ALK could provide significant clinical benefits in malignancies with upregulated ALK activity.
It is recently established that the combined inhibition of PI3-Kinase and mTOR pathways significantly augments crizotinib efficacy to prolong survival in animal models of neuroblastoma. Drugs such as NVP-BEZ235 (Novartis) and LY3023414 (Lilly) are promising drugs under development to block both mTOR and PI3K pathways. Since some forms of neuroblastomas could also exert simultaneous regression, it is also plausible to assume that some pathways involving in dedifferentiation of neural progenitors to neuroblastoma cancer stem cells may trigger expression of antigens, which would cause enhanced recognition by immune cells rather than immunosuppression. Thus, I here propose that combining ALK inhibitors, dual inhibitors of mTOR and PI3K pathways and immunestimulating drugs may provide a powerful synergistic approach in management of neuroblastomas with high risk profile.
Neuroblastoma, the most common extracranial solid cancer in childhood and the most common cancer in infancy can exert a grave course. CD246/ALK (Anaplastic Lymphoma Kinase) is an important protein in neurodevelopment and one of the most important therapeutic targets in neuroblastoma biogenesis. Since the discovery of the oncofetal antigens in 1970's, it is well established that tumors reactivate embryonic genes for growth, invasion, angiogenesis and escape from immuno-surveillance. Crizotinib (Xalkori(R), Pfizer) the aminopyrimine type inhibitor of ALK could provide significant clinical benefits in malignancies with upregulated ALK activity.
It is recently established that the combined inhibition of PI3-Kinase and mTOR pathways significantly augments crizotinib efficacy to prolong survival in animal models of neuroblastoma. Drugs such as NVP-BEZ235 (Novartis) and LY3023414 (Lilly) are promising drugs under development to block both mTOR and PI3K pathways. Since some forms of neuroblastomas could also exert simultaneous regression, it is also plausible to assume that some pathways involving in dedifferentiation of neural progenitors to neuroblastoma cancer stem cells may trigger expression of antigens, which would cause enhanced recognition by immune cells rather than immunosuppression. Thus, I here propose that combining ALK inhibitors, dual inhibitors of mTOR and PI3K pathways and immunestimulating drugs may provide a powerful synergistic approach in management of neuroblastomas with high risk profile.
Friday, October 10, 2014
Selective Tyrosine Kinase Inhibitors and The Concept of "Targeted Therapy of Cancer". Will This Be A Real Cure For Cancer?
With the beginning of the 21th century, a new concept of cancer treatment has emerged, which is aimed to block specific tyrosine kinases coupled with growth factor receptors or oncogene products. The discovery of the imatinib/STI-571 (Gleevec, Glivec) and its phenomenal activity in chronic myeloid leukemia fostered a big interest in discovery of selective tyrosine kinase inhibitors and a great hope arouse that the ultimate therapeutics for cancer will be developed in near future.
Nonetheless, these expectations seem to good to be true, when considering the great plasticity of the cancer cell's transcriptome. Many of the tyrosine kinase inhibitors approved by the FDA for the treatment of solid tumors provide only very limited survival benefits. The main reason of this phenomenon is based on the very fact that the tumor cells do not put their all eggs in one basket. There exist an enourmous alternative of growth factors and apoptosis-blocking proteins , which tumor cells could induce to compensate the noxious effects of anticancer agents targeting only limited signal pathways. Furthermore, these "targeted drugs" are enormously expensive and far from being cost-effective.
Here, a tragedy of self-suffocation exists in our current society. As well known and discussed in many scientific papers and in media, drug companies only interest with patentable molecule sources but not with generic drugs, natural vaccines (such as Coley toxin, which I will discuss later) or phytochemicals, which will not bring "enough" levels of financial benefit for them. This reality leads a vicious cycle to aim discovering more and more "precise targets", yet the cancer's transcriptional defence armamentarium is far more beyond the pharmaceutical companies armamentarium.
In future - whether the pharmaceutical companies like or dislike- , cocktails of simple drugs targeting many diverse signalling pathways of cancer may provide real cures for cancer. Hereby, I do not try to mention that the discovery of selective tyrosine kinase inhibitors or the concept of "targeted therapy" is worthless. Instead, they may constitute powerful members of the combined anti-cancer cocktails in future. My basic point is not to expect ultimate cures for a devastating disease with single shots and single guns.
With the beginning of the 21th century, a new concept of cancer treatment has emerged, which is aimed to block specific tyrosine kinases coupled with growth factor receptors or oncogene products. The discovery of the imatinib/STI-571 (Gleevec, Glivec) and its phenomenal activity in chronic myeloid leukemia fostered a big interest in discovery of selective tyrosine kinase inhibitors and a great hope arouse that the ultimate therapeutics for cancer will be developed in near future.
Nonetheless, these expectations seem to good to be true, when considering the great plasticity of the cancer cell's transcriptome. Many of the tyrosine kinase inhibitors approved by the FDA for the treatment of solid tumors provide only very limited survival benefits. The main reason of this phenomenon is based on the very fact that the tumor cells do not put their all eggs in one basket. There exist an enourmous alternative of growth factors and apoptosis-blocking proteins , which tumor cells could induce to compensate the noxious effects of anticancer agents targeting only limited signal pathways. Furthermore, these "targeted drugs" are enormously expensive and far from being cost-effective.
Here, a tragedy of self-suffocation exists in our current society. As well known and discussed in many scientific papers and in media, drug companies only interest with patentable molecule sources but not with generic drugs, natural vaccines (such as Coley toxin, which I will discuss later) or phytochemicals, which will not bring "enough" levels of financial benefit for them. This reality leads a vicious cycle to aim discovering more and more "precise targets", yet the cancer's transcriptional defence armamentarium is far more beyond the pharmaceutical companies armamentarium.
In future - whether the pharmaceutical companies like or dislike- , cocktails of simple drugs targeting many diverse signalling pathways of cancer may provide real cures for cancer. Hereby, I do not try to mention that the discovery of selective tyrosine kinase inhibitors or the concept of "targeted therapy" is worthless. Instead, they may constitute powerful members of the combined anti-cancer cocktails in future. My basic point is not to expect ultimate cures for a devastating disease with single shots and single guns.
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