Combinatorial Chemistry & High Throughput Screening - Volume 20, Issue 5, 2017

Background & Aim: Cancer is a condition of genetically or environmentally mutated, uncontrollable cell growth that directly affects human morbidity and mortality. Many treatments have been adopted to reduce cancer cell proliferation; however, new mutated developments of some cancer cells have started to show resistance towards current therapies and treatments that cause some drugs to lose their efficacy. Additionally, deleterious side-effects of some hard application methods like radiation therapy, chemotherapy, and surgery are less favorable. Accumulative research effort has revealed that peptides and toxins identified from underutilized natural sources including venomous reptiles, amphibians, insects, arachnids, marine organisms and plants are increasingly being employed in cancer treatment. This demands more peptides / toxins to be identified from underutilized natural sources as an alternative therapeutic approach. Method & Results: Accumulative research effort has revealed that peptides and toxins identified from underutilized natural sources including venomous reptiles, amphibians, insects, arachnids, marine organisms and plants are increasingly being employed in cancer treatment. Secondary structures / pharmacophore modifications have proven to be an important criterion for raising the efficacy level and anticancer effects. Structure specificity and structural-related cytotoxicity have successfully allowed these peptides to target and cause sufficient damage to malignant cells with minimal cytotoxicity effects towards healthy cells. On top of that, some these pure peptides had adopted multiple anticancer mechanisms and demonstrated collective anticancer effects within a single application. Conclusion: Our review exclusively selected peptides and toxins found identified from various natural sources in combating malignant cells, their selectivity towards specific anticancer mechanisms, and the prospective of conjugated peptide as a single entity for a new therapeutic strategy.

Background & Aim: Colorectal cancer (CRC) is a malignant disease whose incidence and mortality rates are greatly influenced by environmental factors. Under-treatment of CRC such as a poor diagnostic evaluation, less aggressive surgery, less intensive chemotherapy results in metastasizing of the primary tumor cells and recurrence of cancer. Prolonged chemotherapy treatment against cancer is hazardous to the patients, which also limits its use in cancer therapy. Current research in developing a novel anti-cancer agent, direct towards finding a better antimetastatic and an anti-invasive drug with reduced side effects. Method & Results: In this direction, plant derived chemical compounds or phytochemical act as a prominent source of new compounds for drug development. Phytochemicals have a multi-action and a multi-target capacity, and has gained attention among the research communities from last two decades. Epidemiological study shows a direct relationship between a diet and CRC development. A diet rich in plant based products such as vegetables, fruits and cereals is known to prevent CRC development. This review is an effort to explore more about the potential phytochemicals in CRC prevention and also in CRC treatment. Conclusion: Here, we have discussed few phytochemicals actively used in CRC research and are in clinical trials against CRC. We have explored more on some of these phytochemicals which can act as a source for new drug or can act as a lead compound for further modifications during the drug development against cancer.

Background: Cancer is a complex disease and a huge threat to human health. The prognosis for some cancer types such as breast cancer has improved dramatically over the past 50 years due to rapid development of surgery, chemotherapy and radiotherapy technologies. However, for many patients bearing unresectable cancers, the prognosis remained poor. For this reason, there is always high demand for newer and better therapeutic reagents in cancer field. But the development of anticancer drugs is risky, lengthy and costly. Not many new anticancer reagents come into market every year. Objective: This review focuses on the latest progress of chemotherapy drug repurposing in cancer research. Conclusion: It is clear from the review of that drug repurposing is faster and cheaper than conventional drug development process. The anticancer efficacy of numerous non-cancer drugs are being tested now. However, not many of them have obtained enough evidence to go into clinical trials for cancer treatment. How to filter the right candidate and narrow the gap between bench and bed remains a hurdle for both conventional and repurposing drug development.

Background & Aim: The ubiquitin-proteasome system (UPS) is the major pathway for degrading the intracellular proteins. The 2004 Nobel Prize in Chemistry was awarded to Rose, Hershko, and Ciechanover to highlight the fundamental importance of UPS. Method & Results: The alterations in this process have been shown to contribute to the cancer progression. Hence, UPS has become a popular target for developing chemotherapeutics against tumours. The application of bortezomib showed high efficiency in treating haematological malignancies by interfering with UPS activity. Many compounds are being screened and evaluated in recent pharmacological advances, either as single agents or in synergy with other drugs, and more to be revealed. Conclusion: In the present review, we exhibit the crucial ingredients involved in UPS and discuss the current situation of small molecules targeting various components of ubiquitination pathway in cancer treatment.

Background & Aim: Photosensitizers are key molecules used in photodynamic cancer therapy (PDT), which is an effective therapeutic modality option for several diseases and nononcological disorders. Due to its lower systemic toxicity and its ability to destroy tumors selectively, PDT has been considered as clinical avenue for the treatment of several cancers. Methods & Results: Three essential elements are involved in a PDT procedure: a photosensitizer, light of a specific wavelength, and singlet oxygen. However, the properties of conventional photosensitizers exhibit some drawbacks that may limit their use. Nanoparticles can provide significant benefits that counter these drawbacks and enable higher efficiency and biosafety. With the development of nanotechnology, nanoparticles have been used to encapsulate photosensitizers to enhance the phototoxic and pharmacokinetic properties of these agents. Conclusion: Here, the main motivation for this review is to summarize recent progress in the development of photosensitizers, in particular, photosensitizers with nanoparticle modifications. In addition, we reviewed the clinical treatment of several diseases using photosensitizers formulated with nanoparticles, with the overall goal of aiding the design and development of novel photosensitizers.

Background: Cancer is a systemic disease. Cancer occurrence is associated with several factors, including cell proliferation, apoptosis, metastasis, tumor microenvironment and immune system. Traditional Chinese medicine (TCM) has been widely used for thousands of years in China for its anti-cancer therapeutic effect. The advantage of using TCM is related to its action on multiple signaling pathways and molecular targets related to cancer, whilst causing few adverse effects. Objective: The review focuses on the most recent studies on TCM through examples that demonstrate the anticancer effects and the mechanisms. Conclusion: The review shows a large number of works which demonstrated that TCM is useful in the treatment of various types of cancers through different mechanisms of action. The results indicate that TCM exerts its anticancer effects through apoptosis induction, proliferation inhibition, metastasis suppression, multidrug resistance reversal and immune function regulation. Moreover, TCM can improve patients' quality of life. The advantage of TCM suggests that TCM may represent a promising therapeutic approach for patients with diverse cancers.

Recently, immunotherapy has attracted more attentions to fight cancer due to its selectivity, long lasting effects, and demonstrated better overall survival and tolerance, when compared to patients treated with conventional chemotherapy or radiotherapy alone. The anti-tumor response of patient with cancer is improved either by increasing the effector cell number, the production of soluble mediators, or by modulating the host's immune checkpoint. Over the last decades, many new approaches in immunotherapy have been developed, such as immune checkpoint inhibitors, chimeric antigen receptor T cells (CART), specific T-cell -receptor T cells (TCRT) and cancer vaccine, some of which has been approved by FDA to treat several cancer types. Among them, immune checkpoint based therapy has shown tremendous promise in both solid and hematological malignancies, and has significantly improved overall survival in patients with advance cancer. Many immuno checkpoints has been discovered and demonstrated. However, there is still lack of a complete summary for them. Thus, the present review focuses on immune checkpoint study and their latest application.

The development of new screening models for cancer therapy is indispensable for the improvement of cancer treatment, and for the creation of alternative possibilities in the field of chemotherapy. Screening models are routinely used to reduce the cost and resources involved in anticancer drug development. The value of any screening model will ultimately be ascertained by its ability to reliably predict the clinical response. Traditional in vivo screening models have been replaced with cell-based screening assays, and these cell-based models are under constant development to better mimic in vivo conditions. In this review, the developmental phases of anticancer screening models are discussed and exemplified, including the two-dimensional, threedimensional, cancer stem cell, and non-mammalian screening models. In addition, the use of new virtual screening tools as a model for anticancer drug development is highlighted.

Background: Tumour microenvironment is recognized as a major determinant of intrinsic resistance to anticancer therapies. In solid tumour types, such as breast cancer, lung cancer and pancreatic cancer, stromal components provide a fibrotic niche, which promotes stemness, EMT, chemo- and radioresistance of tumour. However, this microenvironment is not recapitulated in the conventional cell monoculture or xenografts, hence these in vitro and in vivo preclinical models are unlikely to be predictive of clinical response; which might attribute to the poor predictively of these preclinical drug-screening models. Conclusion: In this review, we summarized recently developed co-culture platforms in various tumour types that incorporate different stromal cell types and/or extracellular matrix (ECM), in the context of investigating potential mechanisms of stroma-mediated chemoresistance and evaluating novel agents and combinations. Some of these platforms will have great utility in the assessment of novel drug combinations and mechanistic understanding of the tumor-stroma interactions.