Hamed Mirzaei

Curcumin: A new candidate for melanoma therapy

Melanoma remains among the most lethal cancers and, in spite of great attempts that have been made to increase the life span of patients with metastatic disease, durable and complete remissions are rare. Plants and plant extracts have long been used to treat a variety of human conditions; however, in many cases, effective doses of herbal remedies are associated with serious adverse effects. Curcumin is a natural polyphenol that shows a variety of pharmacological activities including anti‐cancer effects, and only minimal adverse effects have been reported for this phytochemical. The anti‐cancer effects of curcumin are the result of its anti‐angiogenic, pro‐apoptotic and immunomodulatory properties. At the molecular and cellular level, curcumin can blunt epithelial‐to‐mesenchymal transition and affect many targets that are involved in melanoma initiation and progression (e.g., BCl2, MAPKS, p21 and some microRNAs). However, curcumin has a low oral bioavailability that may limit its maximal benefits. The emergence of tailored formulations of curcumin and new delivery systems such as nanoparticles, liposomes, micelles and phospholipid complexes has led to the enhancement of curcumin bioavailability. Although in vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma, curcumin has not yet been tested against melanoma in clinical practice. In this review, we summarized reported anti‐melanoma effects of curcumin as well as studies on new curcumin formulations and delivery systems that show increased bioavailability. Such tailored delivery systems could pave the way for enhancement of the anti‐melanoma effects of curcumin.

MicroRNAs as potential diagnostic and prognostic biomarkers in melanoma

Melanoma is a life-threatening malignancy with poor prognosis and a relatively high burden of mortality in advanced stages. The efficacy of current available therapeutic strategies is limited, with a survival rate of less than 10%. Despite rapid advances in biomarker-guided drug development in different tumour types, including melanoma, only a very small number of biomarkers have been identified. Recently, microRNAs (miRNAs) have emerged as a molecular regulator in the development and progression of melanoma. Aberrant activation of some known miRNAs, e.g. let-7a and b, miR-148, miR-155, miR-182, miR-200c, miR-211, miR-214, miR-221 and 222, has been recognised to be linked with melanoma-associated genes such as NRAS, microphthalmia-associated transcription factor, receptor tyrosine kinase c-KIT, AP-2 transcription factor, etc. There is accumulating evidence suggesting the potential impact of circulating miRNAs as diagnostic and therapeutic markers in diseases. In addition, miRNAs have turned out to play important roles in drug-resistance mechanisms; suggesting their modulation as a potential approach to overcome chemoresistance. This review highlights recent preclinical and clinical studies on circulating miRNAs and their potential role as diagnosis, and therapeutic targets in melanoma.

Phytosomal curcumin: A review of pharmacokinetic, experimental and clinical studies

Curcumin, a hydrophobic polyphenol, is the principal constituent extracted from dried rhizomes of Curcuma longa L. (turmeric). Curcumin is known as a strong anti-oxidant and anti-inflammatory agent that has different pharmacological effects. In addition, several studies have demonstrated that curcumin is safe even at dosages as high as 8g per day; however, instability at physiological pH, low solubility in water and rapid metabolism results in a low oral bioavailability of curcumin. The phytosomal formulation of curcumin (a complex of curcumin with phosphatidylcholine) has been shown to improve curcumin bioavailability. Existence of phospholipids in phytosomes leads to specific physicochemical properties such as amphiphilic nature that allows dispersion in both hydrophilic and lipophilic media. The efficacy and safety of curcumin phytosomes have been shown against several human diseases including cancer, osteoarthritis, diabetic microangiopathy and retinopathy, and inflammatory diseases. This review focuses on the pharmacokinetics as well as pharmacological and clinical effects of phytosomal curcumin.

Green tea and its anti-angiogenesis effects

The development of new blood vessels from a pre-existing vasculature (also known as angiogenesis) is required for many physiological processes including embryogenesis and post-natal growth. However, pathological angiogenesis is also a hallmark of cancer and many ischaemic and inflammatory diseases. The pro-angiogenic members of the VEGF family (vascular endothelial growth factor family), VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF), and the related receptors, VEGFR-1, VEGFR-2 and VEGFR-3 have a central and decisive role in angiogenesis. Indeed, they are the targets for anti-angiogenic drugs currently approved. Green tea (from the Camellia sinensis plant) is one of the most popular beverages in the world. It is able to inhibit angiogenesis by different mechanisms such as microRNAs (miRNAs). Green tea and its polyphenolic substances (like catechins) show chemo-preventive and chemotherapeutic features in various types of cancer and experimental models for human cancers. The tea catechins, including (-)-epigallocatechin-3-gallate (EGCG), have multiple effects on the cellular proteome and signalome. Note that the polyphenolic compounds from green tea are able to change the miRNA expression profile associated with angiogenesis in various cancer types. This review focuses on the ability of the green tea constituents to suppress angiogenesis signaling and it summarizes the mechanisms by which EGCG might inhibit the VEGF family. We also highlighted the miRNAs affected by green tea which are involved in anti-angiogenesis.

Circulating microRNAs in Hepatocellular Carcinoma: Potential Diagnostic and Prognostic Biomarkers.

Hepatocellular carcinoma (HCC) is one of the most common types of malignancies worldwide. There is little information on the mechanisms involved in the pathogenesis of this disease. Diagnosis of HCC at early stages would be crucial for increasing the survival of patients. Circulating miRNAs have emerged as one of the most attractive tools for an early diagnosis of cancers. Various studies have shown that there is an aberrant expression of miRNAs such as miR-25, miR-375, miR-206, miR-223, miR- 92a, miR-222, miR-1, let- 7f and miR-21 in HCC. Circulating and tissue miRNAs have also key roles in the pathogenesis of HCC by affecting several biologically important pathways such as p53, p21, PTEN, PI3K-AKT, c-Myc and STAT3. In this review, we summarize the current knowledge on the role of miRNAs in diagnosis, prognosis, and treatment of HCC.

Circulating microRNAs as Potential Diagnostic Biomarkers and Therapeutic Targets in Gastric Cancer: Current Status and Future Perspectives

Gastric cancer is among the leading causes of cancer related death worldwide. Patients with gastric cancer are typically asymptomatic, and diagnosed at late stages, supporting the need for the identification of novel prognostic and diagnostic biomarkers. Recently, microRNAs have emerged as molecular regulators that can play key roles in pathogenesis and progression of different malignancies, including gastric cancer. There is a growing body of evidence showing the aberrant activation of some known circulating miRNAs, e.g. let-7a, miR-21, miR-16, miR-93, miR- 103, miR-192a s well as tissue specific-miRNAs, e.g. miR-18a, miR-10b, miR-544, miR-195, miR-378, miR-34a, miR-145 in patients affected by gastric cancer, which involved with modulation of gastric-cancer-associated genes. In addition, there are mounting evidences on the value of miRNAs which are detected to be associated with drug-resistance mechanisms; suggesting their modulation as a potential approach to overcome chemo-resistance. Attuned with these facts, in this review we highlight several recent preclinical and clinical studies performed on circulating and tissue-specific miRNAs as promising biomarkers for detection of patients at early stages, prediction of prognosis, and monitoring of the patients in response to therapy.

Circulating microRNA: a new candidate for diagnostic biomarker in neuroblastoma

Neuroblastoma (NB) is known as a pediatric neoplasm that is associated with variable histopathological features. The use of biomarkers contributes to the monitoring and treatment of various malignancies such as NB. The identification of novel biomarkers such as (epi)genetic biomarkers and microRNAs (miRNAs) in NB has led to better treatments of NB. Among them, miRNAs have emerged as powerful tools in diagnosis, prognosis and therapeutic biomarkers for patients with NB. Circulating biomarkers such as circulating miRNAs present in body fluids (for example, plasma, serum and urine) provided an interesting field of study in NB treatment. The miRNAs have central roles in different pathogenic events in various malignancies such as NB. Hence, these molecules can be a suitable candidate for monitoring and treating NB patients. Here, we summarize some miRNAs as potential prognosis, diagnosis and therapeutic biomarkers in NB.

SiRNA and epigenetic aberrations in ovarian cancer

Ovarian cancer has the most noteworthy lethal rate around gynecologic malignancies, and it is also considered as the fourth most frequent cancer in the woman in world. Two most critical barriers to treatment of ovarian malignancy are absence of early diagnostic markers and advancement of drug resistance after therapy, especially in advanced stages. Various epigenetic changes have been recognized in ovarian cancer. Recent progresses in our understanding of molecular pathogenesis of ovarian malignancy have dramatically provided potential new targets for molecularly targeted therapies. In very recent years, small interfering RNA (siRNA)-mediated gene silencing has been emerging as a novel treatment modality in preclinical studies in the light of its strong gene-specific silencing. Gene suppression mediated by RNA interference (RNAi) significantly suppressed gene expression at the messenger RNA (mRNA) and protein levels. SiRNAs have therapeutic potential for ovarian cancer through various mechanisms. In this review, we not only provide an overview of siRNA designing for epigenetic silencing of genes aberrantly expressed in ovarian cancer but also we will highlight that the epigenetically silenced genes offer new targets for therapeutic approaches based on re-expression of tumor suppressor genes via demethylating and deacetylating drugs.

Epi-Drugs and Epi-miRs: Moving Beyond Current Cancer Therapies

Epigenetic modifications determine phenotypic characteristics in a reversible, stable and genotype-independent manner. Epigenetic modifications mainly encompass CpG island methylation and histone modifications, both being important in the pathogenesis of malignancies. The reversibility of epigenetic phenomenon provides a suitable therapeutic option that is reactivation of epigenetically silenced tumor-suppressor genes. Inhibition of DNA methyltransferase, histone deacetylase and Aurora B kinase, individually or collectively, could feasibly prevent or reverse the impact of epigenetic silencing. MicroRNAs [miRNAs] are an important layer of epigenetic controlling of gene expression, and serve as diagnostic and prognostic biomarkers as well as treatment targets for several types of cancer. miRNAs are involved inepigenetically silencing or activation of genes, tumor suppressor genes and oncogenes, and their modulation opens new horizons for designing novel cancer therapeutic agents.

The potential for circulating microRNAs in the diagnosis of myocardial infarction: a novel approach to disease diagnosis and treatment

MicroRNAs (miRNAs) are a class of small regulatory RNAs that control several cellular processes that may contribute to development of cardiovascular disease (CVD) and the pathophysiological consequences of myocardial infarction (MI). Only a very small-numbers of biomarkers in MI (e.g., Troponin) have been identified, which are sufficiently sensitive, specific and robust. There is growing evidence of an association between specific miRNAs in the pathogenesis of MI. miRNAs are transported within the systemic circulation via exosomes and microparticles, and are therefore detectable in blood, urine, saliva, and other fluid compartments. Dysregulation of myocardial-derived miRNAs, such as miR-1, miR-133, miR-499, and miR-208, have been identified as potential biomarkers in MI. Furthermore, alteration of the levels of some miRNAs during stress-induced apoptosis is reported as a novel therapeutic strategy for cardiac disease. Modulation of mir-24 appears to inhibit cardiomyocyte apoptosis, attenuate infarct size, and reduce cardiac dysfunction. A greater knowledge on the molecular mechanism underlying the functional role of emerging miRNAs, could provide novel insights into identifying of new biomarkers. This review highlights several recent preclinical and clinical studies on the role of miRNAs in myocardial infarction; novel miRNA-based therapeutic approaches for therapeutic intervention, and potential circulating miRNA to be served as biomarkers in patients with suspected MI.