Showing papers by "Aamir Ahmad published in 2014"

Plant polyphenol induced cell death in human cancer cells involves mobilization of intracellular copper ions and reactive oxygen species generation: A mechanism for cancer chemopreventive action

Abstract: Scope Anticancer polyphenolic nutraceuticals from fruits, vegetables, and spices are generally recognized as antioxidants, but can be prooxidants in the presence of copper ions. We earlier proposed a mechanism for such activity of polyphenols and now we provide data in multiple cancer cell lines in support of our hypothesis. Methods and results Through multiple assays, we show that polyphenols luteolin, apigenin, epigallocatechin-3-gallate, and resveratrol are able to inhibit cell proliferation and induce apoptosis in different cancer cell lines. Such cell death is prevented to a significant extent by cuprous chelator neocuproine and reactive oxygen species scavengers. We also show that normal breast epithelial cells, cultured in a medium supplemented with copper, become sensitized to polyphenol-induced growth inhibition. Conclusion Since the concentration of copper is significantly elevated in cancer cells, our results strengthen the idea that an important anticancer mechanism of plant polyphenols is mediated through intracellular copper mobilization and reactive oxygen species generation leading to cancer cell death. Moreover, this prooxidant chemopreventive mechanism appears to be a mechanism common to several polyphenols with diverse chemical structures and explains the preferential cytotoxicity of these compounds toward cancer cells.

Up-regulation of microRNA-10b is associated with the development of breast cancer brain metastasis.

Abstract: Brain metastases from primary breast cancer are difficult to treat and associated with poor prognosis. Our understanding of the molecular basis for the development of such cancers is sparse. We hypothesized that the pro-metastatic microRNA-10b (miR-10b) plays a role in breast cancer brain metastasis. The study cohort comprised of twenty patients with breast cancer and brain metastasis as well as ten control patients (age, stage, and follow-up matched) with breast cancer without brain metastasis. All cases were microscopically reviewed to select tumor blocks with >50% tumor cells. RNA was extracted from formalin fixed paraffin embedded (FFPE) tumor tissue blocks. Expression of miR-10b was analyzed using qRT-PCR. The relevance of miR-10b expression was also tested using human breast cancer cell lines. An increased expression of miR-10b was noted in the primary breast cancer specimens of patients who subsequently developed brain metastasis, compared to those who did not. miR-10b also increased the invasive potential of breast cancer cells in vitro. Wilcoxon signed rank test revealed a statistically significant difference between the paired tumors from breast cancers and brain metastasis (p <0.001). Increased expression of miR-10b appears to be associated with breast cancer brain metastasis. These findings are clinically relevant since miR-10b could serve as a prognostic and/or therapeutic target for anti-metastatic therapy. Identifying molecular signatures of primary breast cancers which have a propensity for brain metastasis is critical for designing novel therapies to counter the development of brain metastasis in patients diagnosed with breast cancer.

Epigenetic regulation of miRNA-cancer stem cells nexus by nutraceuticals

Abstract: Nutraceuticals, the bioactive food components represented by many naturally occurring dietary compounds, have been investigated for a few decades for their numerous beneficial effects, including their anticancer properties. The initial interest in the cancer-preventing/therapeutic ability of these agents was based on their ability to affect multiple signaling pathways that are deregulated in cancer cells. With a shift in the focus of cancer research to the emerging areas such as epigenetic regulation, microRNAs (miRNAs) and the cancer stem cells (CSCs), nutraceuticals initially appeared out of place. However, research investigations over the last several years have slowly but firmly presented evidence that supports a relevance of these agents in modern day research. While nutraceuticals are increasingly being realized to alter miRNA/CSCs expression and function, the molecular mechanism(s) are not very clearly understood. Epigenetic regulation is one mechanism by which these agents exert their anticancer effects. In this focused mini review, we summarize our current understanding of epigenetic regulation of miRNAs and CSCs by nutraceuticals. We discuss both direct and indirect evidences that support such an activity of these compounds.

Cancer chemopreventive pharmacology of phytochemicals derived from plants of dietary and non-dietary origin: implication for alternative and complementary approaches

Abstract: The poor survival statistics of the fatal cancer diseases highlight the need for multiple alternative treatment options. An impressive embodiment of evidence shows that naturally occurring herbal products contain a wide variety of phytochemicals that are regarded as effective cancer protective agents, possessing the ability to retard, block or reverse carcinogenesis. These include dietary agents often termed as nutraceuticals and also the components of non-dietary plants. Many studies in different cell lines, animal models and human epidemiological trials suggest a protective role of a large number of medicinal molecules of herbal origin against different types of cancers. The standard chemotherapeutic regime against cancer faces an unequivocal challenge due to the severity of the side-effects and the post therapeutic management of the disease. Cancer control may therefore benefit from the anti-cancer potential of alternative therapies that may include herbal treatment which nonetheless has been an effective curative strategy reported for a number of diseases since ancient times. In congruence of the above idea, it has been observed that in recent years the demand to utilize alternative approaches to the treatment of cancer is escalating. Additionally, the emergence of resistance to cancer chemotherapy has forced researchers to turn to natural products of herbal and marine origin. Currently, in the armamentarium of anti-cancer pharmaceuticals there are effective plant-derived drugs such as paclitaxel (a complex taxane diterpene isolated from the bark of Taxus brevifolia) which acts as microtubule disruptor. Further there are plant-based dietary agents such as sulphoraphane (an isothiocyanate derived from cruciferous vegetables) and non-dietary agents such as pomiferin (an isoflavonoid from Maclura pomifera) which strongly mimic chemotherapeutic drugs such as vorinostat (suberoylanilidehydroxamic acid) possessing histone diacetylase inhibition activity. In this review we provide a comprehensive outline of the translational potential of plant-based herbal medicine for complementing the current treatment modalities as an adjuvant or alternative therapy for cancer patients.

The therapeutic potential of targeting the epithelial-mesenchymal transition in cancer.

Abstract: Introduction: The process of epithelial-to-mesenchymal transition (EMT) has long been advocated as a process during tumor progression and the acquisition of metastatic potential of human cancers. EMT has also been linked with resistance to cancer therapies.Areas covered: Basic research has provided evidence connecting EMT to increased invasion, angiogenesis and metastasis of cancer cells. A number of signaling pathways such as notch, wnt, hedgehog and PI3K-AKT, and various other individual factors therein, have been intricately connected to the onset of EMT. Here, we provide latest updates on the evidences that further highlight an association between various signaling pathways and EMT, with a focus on therapeutic targets that may have the potential to reverse EMT.Expert opinion: Our understanding of EMT and its underlying causes is rapidly evolving and a number of putative targets have been identified. It is crucial, now than ever before, to design novel translational and clinical studies for the benefit...

Differentially expressed miRNAs in cancer-stem-like cells: markers for tumor cell aggressiveness of pancreatic cancer

Abstract: Pancreatic cancer (PC) is one of the most deadly cancers. The higher mortality is in part due to treatment resistance and early onset of metastasis. The existence of cancer-stem-like cells (CSLCs) has been widely accepted to be responsible for tumor aggressiveness in PC. Emerging evidence suggests that CSLCs have the capacity for increased cell growth, cell migration/invasion, metastasis, and treatment resistance, which leads to poor clinical outcome. However, the molecular role of CSLCs in tumor development and progression is poorly understood. Therefore, mechanistic understanding, and targeted killing of CSLCs may provide a newer therapeutic strategy for the treatment of PC. It has been well accepted that microRNAs (miRNAs) play critical roles during tumor development and progression through deregulation of multiple genes. Moreover, deregulated expression of miRNAs may also play a key role in the regulation of CSLC characteristics and functions. Here we show that isolated CD44(+)/CD133(+)/EpCAM(+) cells (triple-marker-positive cells) from human PC cell lines, MiaPaCa-2 and L3.6pl cells, display aggressive characteristics, such as increased cell growth, clonogenicity, cell migration, and self-renewal capacity, which is consistent with overexpression of CSLC signatures/markers. We also found deregulated expression of over 400 miRNAs, including let-7, miR-30, miR-125b, and miR-335, in CSLCs. As a proof-of-concept, knockdown of miR-125b resulted in the inhibition of tumor cell aggressiveness of CSLCs (triple-marker-positive cells), consistent with the downregulation of CD44, EpCAM, EZH2, and snail. These results clearly suggest the importance of miRNAs in the regulation of CSLC characteristics, and may serve as novel targets for therapy.

Recent progress on nutraceutical research in prostate cancer.

Abstract: Recently, nutraceuticals have received increasing attention as the agents for cancer prevention and supplement with conventional therapy Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer-related death in men in the US Growing evidences from epidemiological studies, in vitro experimental studies, animal studies, and clinical trials have shown that nutraceuticals could be very useful for the prevention and treatment of PCa Several nutraceuticals including isoflavone, indole-3-carbinol, 3,3′-diindolylmethane, lycopene, (−)-epigallocatechin-3-gallate, and curcumin are known to downregulate the signal transductions in AR, Akt, NF-κB, and other signal transduction pathways which are vital for the development of PCa and the progression of PCa from androgen-sensitive to castrate-resistant PCa Therefore, nutraceutical treatment in combination with conventional therapeutics could achieve better treatment outcome in prostate cancer therapy Interestingly, some nutraceuticals could regulate the function of cancer stem cell (CSC)-related miRNAs and associated molecules, leading to the inhibition of prostatic CSCs which are responsible for drug resistance, tumor progression, and recurrence of PCa Hence, nutraceuticals may serve as powerful agents for the prevention of PCa progression and they could also be useful in combination with chemotherapeutics or radiotherapy Such strategy could become a promising newer approach for the treatment of metastatic PCa with better treatment outcome by improving overall survival

The Biological Significance of Zinc in Inflammation and Aging

Abstract: Inflammation is a complex and critical immunological process resulting from host defense mechanisms against trauma, microorganism infection, or other adverse environmental stress or complex combinations of many biological insults sustained by humans. Such inflammatory processes, especially the sustained chronic condition of inflammation, along with inflammation-induced oxidative stress, can lead to irreversible cellular or tissue damage over time, which further contributes to the development of chronic degenerative diseases including cancers. The aging process is another complicated, multifactorial, and inherent biological process that progressively accumulates deleterious damage at the molecular, cellular, tissue, and even organ levels in the body during its maturation following birth, giving rise to alterations in physiological and biochemical functions, and eventually leading to increased vulnerability to diseases including cancers. In this chapter, we will discuss the role of chronic inflammation, oxidative stress, and DNA damage in the aging process, especially in age-related degenerative diseases including cancer. We will also discuss the role of zinc as an anti-inflammatory and antioxidant agent in human health and disease, and its potential role as an anti-aging agent. Finally, we will discuss the detailed mechanisms of the protective action of zinc as a potential anti-aging agent in age-related cellular signaling involving the NF-κB, A20, Nrf2, and p53 pathways.

MicroRNAs in breast cancer therapy.

Abstract: Breast cancer is one of the most common type of cancers as well as a principal cause of cancer-related deaths in women worldwide Although research has provided a better understanding and diagnosis of breast cancer, studies in breast cancer therapeutics are still far from satisfactory Recent research on microRNAs (miRNAs) has implicated these tiny regulatory molecules in progression of breast cancer with the possibility of exploiting them as diagnostic and/or prognostic biomarkers The loss of tumor suppressor miRNAs or overexpression of oncogenic miRNAs can lead to breast cancer tumorigenesis or metastasis However, the next step – linking miRNAs to cancer therapeutics – is still under progression The roles of miRNAs exhibit much potential in breast cancer therapy, but currently need to be further studied and evaluated in order to better understand how to apply laboratory results to clinical medicine Here we provide an update on our current understanding of miRNAs as molecular targets for diagnosis, prognosis and therapy of breast cancers

The Therapeutic Role of MicroRNAs in Human Gliomas

Abstract: Gliomas represent more than a quarter of central nervous system tumors and the vast majority of all malignant brain tumors. Patients diagnosed with a glioma generally have poor prognosis; survival is especially dismal for those harboring high-grade gliomas. With little information on the causes, and limited treatment options, there is an urgent need to better understand the underlying pathophysiology of gliomas as well as validate novel therapeutic avenues. Research in the last few years has focused on microRNAs (miRNAs) as prognostic markers as well as possible therapeutic targets in all cancers, including malignant gliomas. A number of reports have validated use of miRNAs in both in vitro and in vivo experimental models as well as clinical studies. Here, we provide an up-to-date account of the role of several key miRNAs in prognosis and/or therapy of gliomas. In particular, we discuss oncogenic miRNAs such as miRNAs-21, -182, -10b, -106b, -20a and -183 as well as tumor suppressor miRNAs such as miR-34a, -25, -32, -107, -124 and -218 for their reported roles in gliomas. The available literature on miRNAs in gliomas is encouraging and additional translational and clinical studies should be undertaken for realizing the true potential of these small regulatory RNAs.

MicroRNA Targeted Therapy for Overcoming Drug Resistance, Reversal of EMT and Elimination of Cancer Stem Cells in Prostate and Pancreatic Cancer

Abstract: Emerging evidences have demonstrated that miRNAs could directly or indirectly regulate drug resistance through modulation of epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) characteristics. Several miRNAs including let-7, miR-15/16, miR-200, miR-34a, miR-143/145, miR-21, miR-155, miR-197, and miR-221/222 have been found to play crucial roles in the control of drug resistance, EMT, and CSCs in pancreatic and prostate cancers. Therefore, targeting these miRNAs by synthetic agents, nutraceuticals, or synthetic oligonucleotide delivery could become a promising approach for overcoming drug resistance, reversal of EMT, and elimination of CSCs, which would likely lead successful treatment of outcome in patients diagnosed with pancreatic and prostate cancers.

miRNA Targeted Therapy in Lung Cancer

Abstract: MicroRNAs (miRNAs) are small, non-coding RNAs that play critical role in many human diseases, including cancer, where they function as regulatory molecules. Lung cancer remains the leading cause of cancer-related deaths world-wide, which calls for a dire need to elucidate novel targets for early detection and therapy. In recent years, miRNAs have emerged as a class of molecular targets that can potentially be exploited for diagnosis, prognosis as well as therapy of lung cancer. The miRNAs are intricately involved in lung cancer relapse through their regulation of drug resistance and metastasis. This chapter summarizes the state-of-our-knowledge on the role of miRNAs in the progression as well as potential targets for lung cancer therapy. Since this is a rapidly evolving field, we will discuss the novel research published in last 1 year only. It is our hope that the promising pre-clinical results discussed here can quickly find their way to the clinic for the benefit of scores of patients battling with this deadly disease.

The Biological Roles of MicroRNAs in Cancer Stem Cells

Abstract: The concept of cancer stem cells (CSCs) has great clinical implications because small sub-populations of CSCs have been identified in many different tumors that are associated with poor clinical outcome. Sufficient evidence supports central functions of CSCs in tumorigenesis, due to its distinct high potentials of self-renewal, pluripotent differentiation and apoptosis-resistance, contributing to tumor aggressiveness. Therefore, inhibiting/eliminating CSCs will provide a new effective therapeutic approach for the treatment of aggressive tumors. However, the mechanistic roles of CSCs in tumorigenesis are not well understood. MicroRNAs (miRNAs) have been discovered to act as key regulators of gene expression in tumorigenesis. Aberrant expression of miRNAs has been discovered to be related to worse clinical outcome of many different tumors. Evidence shows that these tumor-related miRNAs have key functions in the regulation of cell cycle/proliferation, migration/invasion, chemo-radiation resistance, and metastasis. Moreover, miRNAs may also exert important functions in modulating CSC characteristics; however, its detailed mechanism(s) has not been fully elucidated. Here, we will summarize the potential role of CSC-related miRNAs in CSC function, and will further define the role of genistein in targeting these CSC-related miRNAs.

Molecular Targeted Therapy for Brain Metastatic Breast Cancers: Current Updates

Abstract: Metastatic breast cancers are difficult to manage, and brain metastatic breast cancers are particularly lethal with poor overall survival and outcomes. Our understanding of factors that facilitate brain metastasis of breast cancers is very poor. However, a number of studies in the last few years have focused on brain metastatic breast cancers; a number of therapeutic targets have been tested, and few therapeutic regimes have also been evaluated in phase I/II settings. We discuss here some of the most recent developments in the field. We will limit our discussion to the reports from past one year only to make this article most up-to-date with no repetition of information that has already been reviewed in the available literature.

The Role of miRNAs in the Development of Normal Pancreas and Pancreatic Cancer, and Their Roles in Tumor Progression

Abstract: The microRNAs (miRNAs) have been shown to play important roles in the control of many normal biological processes including cell differentiation and organogenesis During the development of normal pancreas, several miRNAs including miR-375, miR-7, miR-124, etc have been shown to regulate exocrine and endocrine cell differentiation These regulations could in part be mediated through the miRNA-mediated deregulation of transforming growth factor-β, Notch, and Hedgehog signaling, which are the signal transduction pathways that are critically involved in organogenesis during normal development However, deregulated expression of miRNAs could also lead to the development and progression of pancreatic cancer Moreover, miRNAs are also known to regulate the development and maintenance of pancreatic cancer stem cells and epithelial-to-mesenchymal transition phenotypic cells, which are typically responsible for drug resistance, tumor recurrence, and metastasis Therefore, targeting specific miRNAs by oligonucleotide/nanoparticle vector delivery or regulation of miRNAs by natural agents could become novel strategies for the treatment of pancreatic cancer with better treatment outcome in combination with conventional therapeutics

Xia, J.; et al., Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer. Int. J. Mol. Sci. 2012, 13, 9627–9641

Abstract: The authors wish to change Figure 5D of the paper published in IJMS [1]. In Figure 5D, the bands for NF-κB and Bcl-2 are similar with Notch-1 bands. The authors have carefully checked the original files and found that it is an inadvertent mistake in the published version of Figure 5D. Figure 5 is revised as follows. The authors would like to apologize for any inconvenience caused to the readers by these changes.[...]