Muzammal Hussain

Non-steroidal anti-inflammatory drugs, tumour immunity and immunotherapy

Non-steroidal anti-inflammatory drugs (NSAIDs) have received considerable importance in cancer chemoprevention over the last few years. They are now being considered as prospective candidates in cancer immunotherapy because of their striking immune-enhancing impact on various effector elements of anti-tumour immunity on one hand, and to augment the efficacy of different anti-cancer immunotherapeutic strategies on the other. This review specifically discusses the role of NSAIDs in anti-tumour immunity by describing their immunomodulatory effects on different immune cells including tumour-associated macrophages (TAM), dendritic cells (DC), natural killer (NK) cells, T effector cells, and T regulatory cells (Treg). Secondly, the therapeutic perspective of NSAIDs in combination with different anti-cancer immunotherapeutic approaches, in particular the cancer vaccines, tumour-specific monoclonal antibodies, and cytokine-based therapy, has been outlined. At the end, the impact of anti-inflammatories other than NSAIDs on tumour immunity and immunotherapy, and the immunopharmacological potential of selective E-prostanoid (EP) receptor antagonists with respect to cancer immunity have also been discussed briefly.

Aspirin and immune system

The time-tested gradual exploration of aspirins diverse pharmacological properties has made it the most reliable therapeutic agent worldwide. In addition to its well-argued anti-inflammatory effects, many new and exciting data have emerged regarding the role of aspirin in cells of the immune system and certain immunopathological states. For instance, aspirin induces tolerogenic activity in dendritic cells and determines the fate of naive T cells to regulatory phenotypes, which suggests its immunoregulatory potential in relevance to immune tolerance. It also displays some intriguing traits to modulate the innate and adaptive immune responses. In this article, the immunomodulatory relation of aspirin to different immune cells, such as neutrophils, macrophages, dendritic cells (DCs), natural killer (NK) cells, and the T and B lymphocytes has been highlighted. Moreover, the clinical prospects of aspirin in terms of autoimmunity, allograft rejection and immune tolerance have also been outlined.

Artemisinins and immune system.

Artemisinins in combination with other antimalarial drugs remain the mainstay of current antimalarial armamentarium. It is interesting to note that many traditional drugs with antiprotozoal background can wield immunomodulation on the recipients immune system in a positive or negative direction. Artemisinins also attribute immunomodulatory distensions. For instance, they demonstrate predominant immunosuppressive traits toward different immune components by particularly regulating the cellular proliferation and cytokine release, which indicates that they possess some additional mechanisms and features demanding deliberate attentions. This article reviews the data-based immunomodulatory effects of artemisinins on different immune cells including neutrophils, macrophages, splenocytes, T and B cells in conjunction with their therapeutic prospective with regard to inflammation, autoimmunity and delayed-type hypersensitivity.

Hazardous Effects of Titanium Dioxide Nanoparticles in Ecosystem

Although nanoparticles (NPs) have made incredible progress in the field of nanotechnology and biomedical research and their applications are demanded throughout industrial world particularly over the past decades, little is known about the fate of nanoparticles in ecosystem. Concerning the biosafety of nanotechnology, nanotoxicity is going to be the second most priority of nanotechnology that needs to be properly addressed. This review covers the chemical as well as the biological concerns about nanoparticles particularly titanium dioxide (TiO2) NPs and emphasizes the toxicological profile of TiO2 at the molecular level in both in vitro and in vivo systems. In addition, the challenges and future prospects of nanotoxicology are discussed that may provide better understanding and new insights into ongoing and future research in this field.

Design, synthesis, and in vitro biological evaluation of novel 6-methyl-7-substituted-7-deaza purine nucleoside analogs as anti-influenza A agents.

Among many subtypes of influenza A viruses, influenza A(H1N1) and A(H3N2) subtypes are currently circulating among humans (WHO report 2014-15). Therapeutically, the emergence of viral resistance to currently available drugs (adamantanes and neuraminidase inhibitors) has heightened alarms for developing novel drugs that could address diverse targets in the viral replication cycle in order to improve treatment outcomes. To this regard, the design and synthesis of nucleoside analog inhibitors as potential anti-influenza A agents is a very active field of research nowadays. In this study, we designed and synthesized a series of hitherto unknown 6-methyl-7-substituted-7-deaza purine nucleoside analogs, and evaluated for their biological activities against influenza A virus strains, H1N1 and H3N2. From the viral inhibition assay, we identified some effective compounds, among which, compounds 5x (IC50 = 5.88 μM and 6.95 μM for H1N1 and H3N2, respectively) and 5z (IC50 = 3.95 μM and 3.61 μM for H1N1 and H3N2, respectively) demonstrated potent anti-influenza A activity. On the basis of selectivity index, we conceive that compound 5x may serve as a chemical probe of interest for further lead optimization studies with a general aim of developing novel and effective anti-influenza A virus agents.

Implications of MDSCs-targeting in lung cancer chemo-immunotherapeutics

Despite advances in chemotherapy and immunotherapy, advanced lung cancer remains an incurable disease. Novel trends in anticancer therapeutics focus on harnessing the therapeutically-targeted tumor-related immune suppression. In this respect, myeloid-derived suppressor cells (MDSCs) have captured considerable attention in the last few years, as they are vividly implicated in tumor immune escape mechanisms. In this review, we specifically discuss the multifaceted roles of MDSCs in lung tumor microenvironment, encompassing lung tumor growth and progression via suppression of anti-tumor immunity, association with worse prognosis, and hampering the efficacy of lung cancer chemotherapy and immunotherapy. In addition, we also discuss that therapeutic manipulation of MDSCs-targeting, either alone or in combination with chemo- and/or immune-therapeutic regimens, may not only have tumor growth inhibition, anti-angiogenesis and anti-metastasis effects, but may also have the potential to enhance the efficacy of lung cancer chemotherapy and immunotherapy.

Aspirin may do wonders by the induction of immunological self-tolerance against autoimmune atherosclerosis

Induction of immune tolerance is one of the recent novel immunomodulatory strategies to directly intervene the autoimmune-driven atherosclerosis. Aspirin is a prototypic non-steroidal anti-inflammatory drug, which is now being regarded as a life-saver in variety of atherosclerotic cardiovascular complications. Considerable amount of data emerged during last few years clearly suggests that aspirin can cause immunomodulation by several mechanisms, particularly, its ability to induce tolerogenic dendritic cells (DCs) and to upregulate T regulatory (Treg) cells is especially appealing with respect to induction of immunological self-tolerance. Based on this fact, we hypothesize that aspirin, in addition to its anti-inflammatory effect, may also specifically inhibit autoimmune response in atherosclerosis by actively increasing CD4+CD25+FOXP3+Treg cells as well as by inducing tolerogenic DCs which induce hyporesponsiveness in responder naïve T cells. If proved to be correct, this hypothesis will provide an opportunity to medical community with an already available aspirin-based immunotherapeutic approach for inducing immune tolerance against atherosclerosis.

Skp1: Implications in cancer and SCF-oriented anti-cancer drug discovery

In the last decade, the ubiquitin proteasome system (UPS), in general, and E3 ubiquitin ligases, in particular, have emerged as valid drug targets for the development of novel anti-cancer therapeutics. Cullin RING Ligases (CRLs), which can be classified into eight groups (CRL1-8) and comprise approximately 200 members, represent the largest family of E3 ubiquitin ligases which facilitate the ubiquitination-derived proteasomal degradation of a myriad of functionally and structurally diverse substrates. S phase kinase-associated protein 1 (Skp1)-Cullin1-F-Box protein (SCF) complexes are the best characterized among CRLs, which play crucial roles in numerous cellular processes and physiological dysfunctions, such as in cancer biology. Currently, there is growing interest in developing SCF-targeting anti-cancer therapies for clinical application. Indeed, the research in this field has seen some progress in the form of cullin neddylation- and Skp2-inhibitors. However, it still remains an underdeveloped area and needs to design new strategies for developing improved form of therapy. In this review, we venture a novel strategy that rational pharmacological targeting of Skp1, a central regulator of SCF complexes, may provide a novel avenue for SCF-oriented anti-cancer therapy, expected: (i) to simultaneously address the critical roles that multiple SCF oncogenic complexes play in cancer biology, (ii) to selectively target cancer cells with minimal normal cell toxicity, and (iii) to offer multiple chemical series, via therapeutic interventions at the Skp1 binding interfaces in SCF complex, thereby maximizing chances of success for drug discovery. In addition, we also discuss the challenges that might be posed regarding rational pharmacological interventions against Skp1.

ATAD2 in cancer : a pharmacologically challenging but tractable target

ABSTRACT Introduction: ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2’s bromodomain (BRD) may be a very challenging task. ATAD2’s BRD has been predicted as a ‘difficult to drug’ or ‘least druggable’ target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding. Areas covered: In this review, after shedding light on the multifaceted roles of ATAD2 in normal physiology as well as in cancer-etiology, we discuss technical challenges rendered by ATAD2’s BRD active site and the recent drug discovery efforts to find small molecule inhibitors against it. Expert opinion: The identification of a novel low-nanomolar semi-permeable chemical probe against ATAD2’s BRD by recent drug discovery campaign has demonstrated it to be a pharmacologically tractable target. Nevertheless, the development of high quality bioavailable inhibitors against ATAD2 is still a pending task. Moreover, ATAD2 may also potentially be utilized as a promising target for future development of RNAi-based therapy to treat cancers.

Targeting tumor-associated immune suppression with selective protein kinase A type I (PKAI) inhibitors may enhance cancer immunotherapy.

Despite the tremendous progress in last few years, the cancer immunotherapy has not yet improved disease-free because of the tumor-associated immune suppression being a major barrier. Novel trends to enhance cancer immunotherapy aims at harnessing the therapeutic manipulation of signaling pathways mediating the tumor-associated immune suppression, with the general aims of: (a) reversing the tumor immune suppression; (b) enhancing the innate and adaptive components of anti-tumor immunosurveillance, and (c) protecting immune cells from the suppressive effects of T regulatory cells (Tregs) and the tumor-derived immunoinhibitory mediators. A particular striking example in this context is the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A type I (PKAI) pathway. Oncogenic cAMP/PKAI signaling has long been implicated in the initiation and progression of several human cancers. Emerging data indicate that cAMP/PKAI signaling also contributes to tumor- and Tregs-derived suppression of innate and adaptive arms of anti-tumor immunosurveillance. Therapeutically, selective PKAI inhibitors have been developed which have shown promising anti-cancer activity in pre-clinical and clinical settings. Rp-8-Br-cAMPS is a selective PKAI antagonist that is widely used as a biochemical tool in signal transduction research. Collateral data indicate that Rp-8-Br-cAMPS has shown immune-rescuing potential in terms of enhancing the innate and adaptive anti-tumor immunity, as well as protecting adaptive T cells from the suppressive effects of Tregs. Therefore, this proposal specifically implicates that combining selective PKAI antagonists/inhibitors with cancer immunotherapy may have multifaceted benefits, such as rescuing the endogenous anti-tumor immunity, enhancing the efficacy of cancer immunotherapy, and direct anti-cancer effects.