Ashhar S. Ali

Exploitation of protein kinase C : A useful target for cancer therapy

Protein kinase C is a family of serine/threonine kinases. The PKC family is made up of at least 12 isozymes, which have a role in cell proliferation, differentiation, angiogenesis, and apoptosis. Activation of PKC isozyme is dependent on tyrosine-kinase receptors and G-protein-coupled receptors. PKC isozymes regulate multiple signaling pathways including PI3-K/Akt, MAPK, and GSK-3beta. PKC isozymes have variable roles in tumor biology which in part depend on the cell type and intracellular localization. PKC isozymes are commonly dysregulated in the cancer of the prostate, breast, colon, pancreatic, liver, and kidney. Currently, several classes of PKC inhibitors are being evaluated in clinical trials and several challenges in targeting PKC isozymes have been recently identified. In conclusion, PKC remains a promising target for cancer prevention and therapy.

Expression of microRNAs: potential molecular link between obesity, diabetes and cancer.

Clinicians are routinely challenged in their management of cancer patients because of the complexities of obesity and diabetes that are often found as comorbid conditions. Although attention has been given to optimizing treatment planning for these patients, less attention has been given to manage their obesity and diabetes. This suggests that newer, comprehensive approaches must be developed for the treatment of cancer patients as a ‘whole’ rather than as a single disease. While the specific pathologies of each are unique, years of research have indicated intimate molecular links between these chronic diseases. The contribution of sedentary lifestyles and poor dietary habits is recognized; however, the precise molecular links are still not well‐explored. In addition, emerging evidence suggests the important role of microRNAs (miRNAs) in the development and progression of several diseases, yet their roles in linking obesity, diabetes and cancer are only now beginning to be recognized. It is hoped that miRNAs will serve as novel biomarkers and molecular targets for cancer therapy in patients with comorbid conditions. In this review, we discuss the current understanding of the pathobiology of obesity, diabetes and cancer, and document molecular roles of miRNAs linking cancer with obesity and diabetes.

3,3′-diindolylmethane enhances taxotere-induced growth inhibition of breast cancer cells through downregulation of FoxM1†

Emerging evidence suggests that the transcription factor Forkhead Box M1 (FoxM1) is associated with aggressive human carcinomas, including breast cancer. Because elevated expression of FoxM1 has been observed in human breast cancers, FoxM1 has attracted much attention in recent years as a potential target for the prevention and/or therapeutic intervention in breast cancer. However, no information is currently available regarding how downregulation of FoxM1 could be achieved for breast cancer prevention and therapy. Here, we report for the first time that 3,3′‐diindolylmethane (DIM), a nontoxic dietary chemopreventive agent could effectively downregulate FoxM1 in various breast cancer cell lines. Using gene transfection, real‐time reverse transcription‐PCR, Western blotting, invasion and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays, we found that DIM could enhance Taxotere‐induced growth inhibition of breast cancer cells, and decreased invasive capacity of breast cancer cells was observed after either treatment alone or the combination. These effects were associated with downregulation of FoxM1. We also found that knock down of FoxM1 expression by small interfering RNA (siRNA) transfection increased DIM‐induced cell growth inhibition, whereas over‐expression of FoxM1 by cDNA transfection attenuated DIM‐induced cell growth inhibition, suggesting the mechanistic role of FoxM1. Most importantly, the combination treatment significantly inhibited tumor growth in severe combined immunodeficiency (SCID) mice, and the results were correlated with the downregulation of FoxM1 in tumor remnants. We conclude that inactivation of FoxM1 and its target genes by DIM could enhance the therapeutic efficacy of Taxotere in breast cancer, which could be a useful strategy for the prevention and/or treatment of breast cancer.

The role of cancer stem cells and miRNAs in defining the complexities of brain metastasis

Researchers and clinicians have been challenged with the development of therapies for the treatment of cancer patients whose tumors metastasized to the brain. Among the most lethal weapons known today, current management of brain metastases involves multiple therapeutic modalities that provide little, if any, for improving the quality of life and overall survival. Recently the role of cancer stem cells (CSCs) in the development of cancer has been studied extensively, and thus its role in the prognosis, diagnosis, and treatment is now being investigated even in the realm of brain metastasis (BM). Recognizing the molecular make‐up of CSCs as well as understanding the role of these cells in resistance to treatment modalities is expected to benefit cancer patients. Additionally, past decade has witnessed an increase in awareness and understanding of the role of microRNAs (miRNAs) in various cancer types, and the deregulation miRNAs are critically important for the regulation of genes during the development and progression of human malignancies. The role miRNAs in BM is being investigated, and has also shown tremendous promise for future research. In this review, we discuss the problem and lethality of brain metastases and the current state of management, and further provide insight into novel avenues that are worth considering including the biological complexities of CSCs and miRNAs for designing novel therapies. J. Cell. Physiol. 228: 36–42, 2013.

A novel copper complex of 3‐benzoyl‐α methyl benzene acetic acid with antitumor activity mediated via cyclooxygenase pathway

Pancreatic cancer (PC) is characterized as one of the deadliest malignancies and its treatment is a great challenge to clinical oncologists. Expression of COX‐2 is detectable in 75% of PCs among which 50% showed overexpression, suggesting the importance of COX‐2 enzyme and its metabolic product prostaglandin E2 (PGE2) in PC. Here the authors report the synthesis and biological activity of a novel COX‐2 inhibitor, FPA‐306, and its effects on PC cells with different levels of COX‐2 expression. Using MTT assay, the authors found a significant growth inhibition of BxPC‐3 cells treated by FPA‐306 with an IC50 of 10 μmol/L, which was lower than that of ketoprofen (IC50 = 35.4 μmol/L) and celecoxib (IC50 > 100 μmol/L). There was no such effect found in MIAPaCa cell line, which does not express COX‐2. The authors also found dose dependent reduction in cell survival and induction of apoptosis by FPA‐306 treatment in BxPC‐3 cells but not in MIAPaCa cells. These results were correlated with apoptosis data and secreted PGE2 levels. The molecular modeling of FPA‐306 in the COX‐2 active site showed that FPA‐306 is potentially able to inhibit the activity of enzyme by blocking the active site, thereby resulting in decreased PGE2 production. The authors also found a significant reduction of COX‐2 at the mRNA and protein levels together with downregulation of NF‐κB DNA binding activity and its downstream genes, Bcl‐2 and survivin. These results suggest that FPA‐306 is an effective and potent agent in inhibiting the growth of PC cells.

MicroRNAs in Breast Cancer Research: Progress and Promise

Over the years, remarkable progress has been made in regards to our understanding of breast cancer biology and consequently the development of novel treatments. One idea that has proven to be immensely valuable is the use of microRNAs (miRNAs) in cancer diagnosis, prognosis, and even for treatment. The miRNAs are short RNA molecules that are able to post-transcriptionally regulate the expression of genes at multiple levels. Past and current research has continued to classify miRNAs as either highly or rarely expressed in cancer cells in relation to their normal non-cancerous counterparts. This classification is also used to organize the various miRNAs as either tumor suppressing or oncogenic. For example, aberrant expression of certain miRNAs is widely accepted to signify different stages of cancer. This chapter summarizes our current understanding of the role of miRNAs in cancer, while enlightening the readers with the role of specific miRNAs in breast cancer development and progression, and their exploitation for designing innovative therapeutic strategies.

Delirium Induced by a New Synthetic Legal Intoxicating Drug: Phenazepam

Phenazepam is a long-acting benzodiazepine that is not currently a controlled substance in theUnited States. It is marketed as an air freshener that is labeled “not for human consumption” in an attempt to avoid scrutiny by legal authorities. Such drugs of abuse have been termed synthetic legal intoxicating drugs or “SLIDs.” In this article, we report the first case of phenazepaminduced delirium in the United States. This adds to the limited published data on SLIDs and provides consultation-liaison psychiatrists with new information on the necessity of screening for such drugs in cases of suspected substance-induced delirium.

MicroRNAs in Cancer Invasion and Metastasis

The field of cancer research has received invaluable gifts over the last few decades through novel innovations in molecular understanding and drug development. One area that is currently receiving much attention is that of microRNAs (miRNAs). The miRNAs are small, non-coding molecules that inhibit gene expression post-transcriptionally, and emerging evidence suggests that miRNAs are involved in cell growth, differentiation, and apoptosis. These developments could serve as the catalyst for further research focusing on finding a possible molecular link between miRNAs and cancer. This revolutionary research in the field of cancer has shown great promise in understanding the regulatory role of miRNAs in the development and progression of cancer, emphasizing its biochemical and pathological implications, and in particular, its significant role in cancer invasion and metastasis. For example, it has now been widely accepted that certain miRNAs are oncogenic while others act as tumor suppressors. Additionally, studies have shown that miRNAs can be used to alter sensitivity of drug-resistant tumor cells in order to improve the effects of conventional therapeutics. Furthermore, natural agents have been shown to alter miRNA expression, leading to possible inhibition of cancer cell growth and induction of apoptosis, which may contribute to the inhibition of tumor cell migration, invasion, and metastases. Therefore, selective up- and down-regulation of miRNAs holds a great promise for cancer therapy especially for those patients with invasive and metastatic disease. In this chapter, we will summarize the state of our knowledge regarding the role of miRNAs in cancer invasion and metastasis, and will also provide some information on how miRNAs could be regulated for therapeutic interventions.

Legendary signs in infective endocarditis: revisited

A 65-year-old man presented to the emergency department complaining of 1-month history of back pain. He also noted fatigue, night sweats, blurry vision and 10 lb weight loss. He recalls dental cleaning recently, but denied any other medical history. He was afebrile and hemodynamically stable. Physical examination showed non-tender …

Migraine With Neurological Features in a Scuba Diver With a Patent Foramen Ovale.

Neurologic complications of decompression sickness have been observed for over half of a century. Little is known, however, about the risk of diving in patients that suffer from migraine with aura (MWA). We report the case of a pediatric patient with a history of migraine with aura, who was later found to have a PFO, who developed headache with neurological symptoms during a scuba diving lesson.