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1.
The TRPCs, Orais and STIMs in ER/PM Junctions.
Shin, DM, Son, A, Park, S, Kim, MS, Ahuja, M, Muallem, S
Advances in experimental medicine and biology. 2016;:47-66
Abstract
The Ca(2+) second messenger is initiated at ER/PM junctions and propagates into the cell interior to convey the receptor information. The signal is maintained by Ca(2+) influx across the plasma membrane through the Orai and TRPC channels. These Ca(2+) influx channels form complexes at ER/PM junctions with the ER Ca(2+) sensor STIM1, which activates the channels. The function of STIM1 is modulated by other STIM isoforms like STIM1L, STIM2 and STIM2.1/STIM2β and by SARAF, which mediates the Ca(2+)-dependent inhibition of Orai channels. The ER/PM junctions are formed at membrane contact sites by tethering proteins that generate several types of ER/PM junctions, such as PI(4,5)P2-poor and PI(4,5)P2-rich domains. This chapter discusses several properties of the TRPC channels, the Orai channels and the STIMs, their key interacting proteins and how interaction of the STIMs with the channels gates their activity. The chapter closes by highlighting open questions and potential future directions in this field.
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2.
Designing a broad-spectrum integrative approach for cancer prevention and treatment.
Block, KI, Gyllenhaal, C, Lowe, L, Amedei, A, Amin, ARMR, Amin, A, Aquilano, K, Arbiser, J, Arreola, A, Arzumanyan, A, et al
Seminars in cancer biology. 2015;(Suppl):S276-S304
Abstract
Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.
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3.
Evasion of anti-growth signaling: A key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds.
Amin, ARMR, Karpowicz, PA, Carey, TE, Arbiser, J, Nahta, R, Chen, ZG, Dong, JT, Kucuk, O, Khan, GN, Huang, GS, et al
Seminars in cancer biology. 2015;:S55-S77
Abstract
The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting.
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4.
Mycobacterial signaling through toll-like receptors.
Basu, J, Shin, DM, Jo, EK
Frontiers in cellular and infection microbiology. 2012;:145
Abstract
Studies over the past decade have helped to decipher molecular networks dependent on Toll-like receptor (TLR) signaling, in mycobacteria-infected macrophages. Stimulation of TLRs by mycobacteria and their antigenic components rapidly induces intracellular signaling cascades involved in the activation of nuclear factor-κB and mitogen-activated protein kinase pathways, which play important roles in orchestrating proinflammatory responses and innate defense through generation of a variety of antimicrobial effector molecules. Recent studies have provided evidence that mycobacterial TLR-signaling cross talks with other intracellular antimicrobial innate pathways, the autophagy process and functional vitamin D receptor (VDR) signaling. In this article we describe recent advances in the recognition, responses, and regulation of mycobacterial signaling through TLRs.
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5.
The medicinal chemistry of theragnostics, multimodality imaging and applications of nanotechnology in cancer.
Majumdar, D, Peng, XH, Shin, DM
Current topics in medicinal chemistry. 2010;(12):1211-26
Abstract
Targeted imaging of cancer is crucial to modern-day cancer management. This review summarizes the current status and future prospects of targeted cancer imaging with MRI, PET, SPECT, CT, and optical imaging techniques. It describes various approaches of cancer imaging and therapy, based on targeting of integrins, somatostatin receptor, epidermal growth factor receptor (EGFR), Her-2/neu receptor, glucose transporter (GLUT), folate receptor, steroid receptor. It also discusses the applications of nanotechnology in imaging and therapy of cancer. Techniques for imaging of cancer in multiple modalities, using a single agent in a single session, have been developed, and this technique is known as 'multimodality imaging'. In order to develop target-specific imaging probes, various targeting ligands, such as small molecules, antibodies, peptides and aptamers have been used. These new imaging agents will help to develop cancer imaging probes that are highly target specific, biocompatible, have high sensitivity, give high signal to noise ratio, and have optimum pharmacokinetic and pharmacodynamic profiles. In another approach, novel agents have been synthesized, suitable for use in imaging as well as in therapy, and they are known as 'theragnostic (or theranostic) agents'. Multidisciplinary approaches and collaborative research efforts from chemists, biologists, biomedical engineers, pharmaceutical scientists, and medical doctors will lead to the discovery of clinically useful imaging and therapeutic agents that can diagnose, prevent, and cure cancer.
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6.
Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy.
Peng, XH, Qian, X, Mao, H, Wang, AY, Chen, ZG, Nie, S, Shin, DM
International journal of nanomedicine. 2008;(3):311-21
Abstract
Magnetic iron oxide (IO) nanoparticles with a long blood retention time, biodegradability and low toxicity have emerged as one of the primary nanomaterials for biomedical applications in vitro and in vivo. IO nanoparticles have a large surface area and can be engineered to provide a large number of functional groups for cross-linking to tumor-targeting ligands such as monoclonal antibodies, peptides, or small molecules for diagnostic imaging or delivery of therapeutic agents. IO nanoparticles possess unique paramagnetic properties, which generate significant susceptibility effects resulting in strong T2 and T*2 contrast, as well as T1 effects at very low concentrations for magnetic resonance imaging (MRI), which is widely used for clinical oncology imaging. We review recent advances in the development of targeted IO nanoparticles for tumor imaging and therapy.
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7.
Nanotechnology for targeted cancer therapy.
Wang, MD, Shin, DM, Simons, JW, Nie, S
Expert review of anticancer therapy. 2007;(6):833-7
Abstract
Cancer nanotechnology is currently under intense development for applications in cancer imaging, molecular diagnosis and targeted therapy. The basic rationale is that nanometer-sized particles, such as biodegradable micelles, semiconductor quantum dots and iron oxide nanocrystals, have functional or structural properties that are not available from either molecular or macroscopic agents. When linked with biotargeting ligands, such as monoclonal antibodies, peptides or small molecules, these nanoparticles are used to target malignant tumors with high affinity and specificity. In the 'mesoscopic' size range of 5-100 nm in diameter, nanoparticles also have large surface areas and functional groups for conjugating to multiple diagnostic (e.g., optical, radioisotopic or magnetic) and therapeutic (e.g., anticancer) agents. Recent advances have led to multifunctional nanoparticle probes for molecular and cellular imaging, nanoparticle drugs for targeted therapy, and integrated nanodevices for early cancer detection and screening. These developments have opened exciting opportunities for personalized oncology in which cancer detection, diagnosis and therapy are tailored to each individual's molecular profile, and also for predictive oncology, in which genetic/molecular information is used to predict tumor development, progression and clinical outcome.
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8.
Moving toward bioadjuvant approaches to head and neck cancer prevention.
Saba, NF, Hammond, A, Shin, DM, Khuri, FR
International journal of radiation oncology, biology, physics. 2007;(2 Suppl):S132-5
Abstract
Head and neck squamous cell carcinoma affects >45,000 Americans annually. Patients who are successfully treated for their primary tumor are at high risk of developing a second primary tumor, making effective preventive strategies highly desirable for this disease. Although a landmark study in 1990 suggested some benefit of high-dose retinoids in head and neck cancer prevention, subsequent trials using more tolerable doses have shown limited clinical success. Newer preventive strategies have included bioadjuvant therapy combining retinoids with interferon and alpha-tocopherol, combinations of molecularly targeted agents, and oncolytic viruses. Furthermore, considerable evidence has supported a cancer protective role for several nutrients, including green tea and curcumin analogs. Natural compounds such as these with favorable long-term safety profiles might be particularly suited to the cancer prevention setting, in which patients will usually tolerate only moderate risk and toxicity.
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9.
Advances in chemoprevention of head and neck cancer.
Rhee, JC, Khuri, FR, Shin, DM
The oncologist. 2004;(3):302-11
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Abstract
Head and neck squamous cell carcinoma is a devastating disease with a poor outcome in advanced stages, accounting for approximately 3% of all malignancies, with an estimated 37200 new cases and 11000 deaths annually in the U.S. Second primary tumors are estimated to occur at an annual rate of 3%-10% and are significant threats to long-term survivors. Chemoprevention is an appealing strategy, and its success has been demonstrated in breast cancer and familial adenomatous polyposis. High-dose retinoids have been shown to be active against oral premalignant lesions and in prevention of second primary tumors in the head and neck. New targets include the epidermal growth factor receptor, cyclooxygenase-2, and other molecular targets. Challenges in future head and neck cancer chemoprevention investigations include achieving long-lasting efficacy with retinoids and/or new agents, and determining the optimal dose and duration of therapy while maintaining acceptable toxicities.