Anti-Cancer Agents in Medicinal Chemistry (v.13, #3)

Advances in the Systemic Treatment of Neuroendocrine Tumors in the Era of Molecular Therapy by Roland Leung, Brian Lang, Hilda Wong, Joanne Chiu, Wan K. Yat, Tony Shek, Woo Y. Cho, Lo C. Yau, Thomas Yau (382-388).
Neuroendocrine tumors (NETs) are heterogeneous in underlying tumor biology and clinical presentations. They are generally classified according to their degree of differentiation and sites of origin. Moreover, NETs are further characterized by their secreted bioactive neuroamine. The treatment paradigm used to be surgical intervention in early disease and mostly palliative nature in the metastatic setting. With an increase in the understanding of the molecular signaling pathways involved in tumor growth, there are various emerging treatment options for patients with advanced NETs. Somatostatin analogs have both anti-tumor effects as well as symptom palliation associated with the secreted neuropeptides. Peptide-radio-receptor treatment (PRRT) using radio-labeled peptides which binds to somatostatin receptor is a useful anti-tumor treatment but limited by general availability. Sunitinib, a multi-targeted tyrosine kinase inhibitor, has recently been shown to improve the survival of pancreatic NETs patients. Similarly, the use of an mTOR inhibitor — everolimus, either alone or in combination with somatostatin analogs have demonstrated encouraging efficacy in treating advanced NETs. The success of these two agents in pancreatic NETS supports the notion that targeting angiogenesis and/or PI3K/AKT/mTOR pathway is an important strategy for making therapeutic advances in this disease. There are now many ongoing trials in exploring the role of other novel agents in treating patients with pancreatic NETs or carcinoid. The major plaguing problem in this era is the differential response to biological agents amongst NETs of different anatomical origins. Pancreatic NETs are generally more responsive to both chemotherapy and targeted agents than NETs of other sites. Thus, the development of potential predictive and prognostic biomarkers to tailor various molecular therapies to different NETs populations is a major unmet need.

Current development of molecular targeted therapies in oncology is particularly active. This paper is a review of the recent advances in the field of molecular targeted therapies for head and neck squamous cell carcinoma (HNSCC). We analyze not only the recently published and ongoing clinical trials, but also the relevant preclinical studies, in order to identify the future directions of research in the field of HNSCC. As epidermal growth factor receptor (EGFR) signaling pathway plays a key role in the growth of HNSCC, EGFR, with its downstream effectors, represents the main target of the new therapeutic agents currently in development. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of HNSCC in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic disease, in association with platinum-based chemotherapy. Future advances are expected with the integration of cetuximab and other anti-EGFR agents into induction chemotherapeutic regimens or in association with concurrent chemoradiotherapy for locally advanced tumors. Besides EGFR inhibition, new molecular targeted therapies such as mTOR, Src kinase, or IGF-1R inhibitors, acting on other activated molecular signaling pathways, are being developed. As these innovative molecules are beginning to be used in clinical practice, the identification of predictive markers for efficacy and toxicity is now a crucial issue.

Multifunctionalized Microbubbles for Cancer Diagnosis and Therapy by Hao Li, Jianhao Wang, Gang Huang, Ping Wang, Rongqin Zheng, Chao Zhang, Qing Jiang (403-413).
Microbubbles (MBs) are gas-filled hollow microparticles. Under the ultrasound field, the difference of acoustic characteristics between gas and plasma in the blood vessel will cause strong impedance mismatch and echogenicity to enhance ultrasonic grey scale imaging. The linear or nonlinear resonance of MB shell in the ultrasound field would lead to repeated expansion-contraction till destruction. In this case, the pre-loaded drug in the MB shell will be released in an accelerated manner triggered by the ultrasound at a probe–given site. Sonoporation effect of the cell membrane would also help increase the uptake of substances into cells. This paper is dedicated to review recent developments on MBs, especially multifunctionalized MBs, as a potential drug/gene delivery microdevices for both diagnosis and therapy of malignant tumors.

Cytotoxicity and Cell Death Mechanisms Induced by a Novel Bisnaphthalimidopropyl Derivative against the NCI-H460 non-small Lung Cancer Cell Line by Raquel T. Lima, Gemma A. Barron, Joanna A. Grabowska, Giovanna Bermano, Simranjeet Kaur, Nilanjan Roy, M. Helena Vasconcelos, Paul K.T. Lin (414-421).
Some polyamine derivatives, namely the bisnaphthalimidopropyl polyamines (BNIPPs) may have potential as anticancer drugs. Indeed, previous work from some of us had shown that the ability of these molecules to bind to DNA may contribute to their cytotoxicity. However, their precise mode of action has not been fully understood. In the present work, we report for the first time the effect of the previously synthesised compounds, BNIPDaCHM and NPA, together with a new BNIP derivative (BNIP-3,4-DaDPM) in the in vitro growth of a non-small cell lung cancer cell line (NCI-H460). In addition, for the most potent compound (BNIPDaCHM), its activity as sirtuin inhibitor was investigated in vitro and further confirmed in silico. Results in the NCI-H460 cells showed that, from the compounds tested, BNIPDaCHM was the most potent (GI50 of 1.3 μM). In addition, a concentration-dependent alteration in the normal NCI-H460 cell cycle profile was observed following treatment with BNIPDaCHM as well as an increase in the sub-G1 peak (suggestive of apoptotis). This effect was further supported by Annexin V/PI staining and by analysing the expression of proteins related to apoptosis (cleaved PARP and Caspase-3) by Western blot. It was also observed that BNIPDaCHM inhibited the activity of SIRT2 in vitro, but not of SIRT1. Accordingly, this compound also caused a small increase in tubulin acetylation in NCI-H460 cells. To determine the binding potential of BNIPDaCHM on hSIRT2 and to further validate its inhibitory action, in silico docking studies were carried out, which revealed that BNIPDaCHM is composed of an entirely new SIRT2- inhibiting structural scaffold. In conclusion, this study indicates that BNIP derivatives with a novel structural backbone, such as BNIPDaCHM, may have potential as building blocks for novel antitumour agents which might selectively bind to hSIRT-2.

Heterocyclic Chalcone Analogues as Potential Anticancer Agents by Vikas Sharma, Vipin Kumar, Pradeep Kumar (422-432).
Chalcones, aromatic ketones and enones acting as the precursor for flavonoids such as Quercetin, are known for their anticancer effects. Although, parent chalcones consist of two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl system, various synthetic compounds possessing heterocyclic rings like pyrazole, indole etc. are well known and proved to be effective anticancer agents. In addition to their use as anticancer agents in cancer cell lines, heterocyclic analogues are reported to be effective even against resistant cell lines. In this connection, we hereby highlight the potential of various heterocyclic chalcone analogues as anticancer agents with a brief summary about therapeutic potential of chalcones, mechanism of anticancer action of various chalcone analogues, and current and future prospects related to the chalcones-derived anticancer research. Furthermore, some key points regarding chalcone analogues have been reviewed by analyzing their medicinal properties.

Biology and Medicinal Chemistry Approaches Towards Various Apoptosis Inducers by Vivek K. Vyas, Chetan Chintha, Mitul R. Pandya (433-455).
Apoptosis is a genetically in-built process whereby organisms remove unwanted cells. Apoptosis can serve as a regulatory and defense mechanism in the formation of the shape and size of the human body and also to eradicate surplus amount of cells. The regulation of apoptosis is relevant and differentiates between a normal cells of body and cancer cells by loss of control. Apoptosis being an intricate process regulated by much more than just a biological mechanism. The induction of the apoptosis manifests the control on the tumour size and number of tumour cells hence establishing the application of apoptotic inducers as vital components in the treatment of cancer. During apoptosis, cells die in a controlled and regulated fashion which makes apoptosis distinct from necrosis (uncontrolled cell death). Protein components and regulators for apoptosis signaling pathways can involve the mitochondria (intrinsic pathway) or signal through death receptors (extrinsic pathway). Many different drug and gene therapy approaches are being tested for initiating apoptosis. Resistance to apoptosis is considered a hallmark of cancer. Therapeutic approaches attempted to date include traditional small molecules, antisense oligonucleotides, monoclonal antibodies, recombinant proteins and several classes of chemical compounds discussed in this review. These compounds may serve as precursor molecules for more effective drugs, all aimed at developing clinically effective therapeutics, targeting key apoptosis regulatory mechanism. This review will discuss the current understanding of apoptosis induced by various chemical agents and highlighting the role of apoptosis inducing agents as emerging opportunities for cancer therapy.

Quinones Derived from Plant Secondary Metabolites as Anti-cancer Agents by Jin-Jian Lu, Jiao-Lin Bao, Guo-Sheng Wu, Wen-Shan Xu, Ming-Qing Huang, Xiu-Ping Chen and Yi-Tao Wang (456-463).
Quinones are plant-derived secondary metabolites that present some anti-proliferation and anti-metastasis effects in various cancer types both in vitro and in vivo. This review focuses on the anti-cancer prospects of plant-derived quinones, namely, aloe-emodin, juglone, β-lapachol, plumbagin, shikonin, and thymoquinone. We intend to summarize their anti-cancer effects and investigate the mechanism of actions to promote the research and development of anti-cancer agents from quinones.

Endocrine therapy has developed rapidly and become most effective and clearly target form of adjuvant therapy for hormone sensitive breast cancer. Adjuvant endocrine therapy for breast cancer can be given after surgery or radiotherapy, and also prior, or subsequent to chemotherapy. Current commonly used drugs for adjuvant endocrine therapy can be divided into following three classes: selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and selective estrogen receptor down-regulators (SERDs). Unfortunately, tumor cells may develop resistance to endocrine therapy, which become a major obstacle limiting the success of breast cancer treatment. The complicated crosstalk, both genomic and nongenomic, between estrogen receptor and growth factors was considered to be a crucial factor contributing to endocrine resistance. However, the progression of resistance to endocrine therapy supposes to be a progressive, step-wise procedure and the underlying mechanism remains unclear. In this review, we would summarize the possible biology and molecular mechanisms that underlie endocrine resistance, and also some novel strategies to overcoming this issue.

Histone Deacetylase Inhibitors as Potential Therapeutic Agents for the Treatment of Malignant Mesothelioma by Patroklos Katafygiotis, Constantinos Giaginis, Efstratios Patsouris, Stamatios Theocharis (476-482).
Histone deacetylase inhibitors (HDACIs) represent one of the most promising, recently developed classes of anticancer agents already approved by the U.S. FDA. The effectiveness of these new drugs has currently being explored in a variety of cancer cell lines, in vitro, animal models, in vivo, as well as in clinical trials. Malignant mesothelioma (MM) is a rare aggressive malignancy with a median overall survival of 12 months when the current chemotherapy regimen, cisplatin-pemetrexed, is applied. This disappointing overall survival has encouraged the experimental use of novel pharmaceutical agents, including HDACIs. In this aspect, the present review is aimed to summarize the existing data regarding the potential utility of HDACIs as therapeutic targets for the treatment of MM. Taking into consideration the research investigations so far, both in vitro and in vivo studies have documented encouraging results. Promising results are also being expected by ongoing clinical trials that concern combination of chemotherapy with HDACIs against MM.

Mutation detection in samples from thyroid cancer with the addition of BRAF mutation, and also the detection of RAS, RET/PTC, and PAX8/PPARγ mutations, may also contribute to cancer diagnosis. On the other hand, the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway) and PI3K/Akt (lipid kinase phoshoinositid-3-kinase signaling pathway) play an important role in the transmission of cell signals. The genes, coding the signaling cascade proteins (RET, RAS, BRAF, PI3K, PTEN, AKT), are mutated or aberrantly expressed in thyroid cancer derived from follicular thyroid cells. Genetic and epigenetic alternations, concerning MAPK/ERK and PI3K/Akt signaling pathways, contribute to their activation and interaction as a consequence of malignant follicular cell transformation. The understanding of this molecular mechanism provides access to novel molecular prognostic and therapeutic strategies for inhibiting the oncogenic activity of the signaling pathways. This ability to investigate tumour biology allows for the selection of different drugs. Nowadays the most relevant are treatments directed to tyrosine kinase receptors that bind for a wide variety of ligands and are frequently mutated and induce a constitutive activation such that a chimerical protein expression takes place in follicular cells in the domain of RET, as well as in other receptors. Many molecules such as: motesanib, sorafenib, vandetanib, sunitinib, XL-184, imatinib, axitinib, pazopanib, lenvatinib, combretastatin, gefitinib, cetuximab, bortezomib and thiazoldonedione have been developed. Some of them also can act in receptors of vascular endothelial growth factor and epidermal growth factor receptors. Information obtained through cytological or biopsy samples permits the study of complex metabolic or genetic pathways, thus providing researchers with a high throughput tool for elucidating changes in the global expression patterns seen in tumour cells and allowing for different therapeutic strategies in thyroid cancer which take into account the predominant altered pathways observed in these samples.

Redox-inactive Analogue of Tocotrienol as a Potential Anti-cancer Agent by Tomohiro Yano, Ayami Sato, Miki Sekine, Nantiga Virgona, Masako Ota (496-501).
Vitamins are prominent among natural or endogenous compounds that are considered to be beneficial for both prevention and therapy of various human ailments. The vitamin E group of compounds composed of tocopherol and tocotrienol isoforms, has been subsequently proven to have health benefits including antioxidant and related protective properties. However, individual isoforms exhibit a wide-range of antioxidant potencies. Tocotrienol (T3) displays powerful anticancer activity that is often not exhibited by tocopherols, by modulating multiple intracellular signaling pathways associated with tumor cell proliferation and survival. The anticancer effect of T3 remains not fully understood but generally is mediated independently of its antioxidant activity. Further we have synthesized a new redox-inactive analogue of T3, 6-O-carboxypropyl-α-tocotrienol (T3E) showing considerable promise for stronger anticancer potency than its mother compound. In this mini-review, we particularly focus upon the anticancer action of the above active components of vitamin E and describe current research on the anticancer effects of T3 irrespective of antioxidant activity.

NADPH Oxidases NOXs and DUOXs as Putative Targets for Cancer Therapy by Urbain Weyemi, Christophe E. Redon, Palak R. Parekh, Corinne Dupuy, William M. Bonner (502-514).
Reactive oxygen species (ROS) form a class of molecules with both positive and negative impacts on cellular health. Negatively, ROS may react with cellular constituents including proteins, lipids, and DNA to generate an array of oxidative lesions. These lesions may compromise genome stability which is critical for long-term cellular homeostasis and healthy progeny. Paradoxically, ROS also function as strong signalling molecules that mediate various growth-related responses, so their presence is also essential for cellular metabolism. While ROS are generated in an unregulated manner by physical stresses such as exposure to ionizing radiation and biochemical malfunctions such as mitochondrial leakage, cells also contain the NADPH oxidases NOXs and DUOXs, which specifically generate ROS in a wide variety of tissues. While the NOXs/DUOXs may be involved in maintaining optimal cellular redox levels, there is also accumulating evidence that NADPH oxidases-derived ROS may elevate the risk for genomic instability and cancer. Cancer cells may produce high levels of ROS, and in some cases, the source of these ROS has been linked to NOX/DUOX deregulation as reported for prostate cancer (NOX1 and NOX5), melanoma and glioblastoma (NOX4) among others. In addition, recent studies reveal that targeting NADPH oxidases with NOXs inhibitors may impair tumor growth in vivo; indicating that these proteins may be useful targets in future clinical strategies to fight cancer. This review provides an overview of the current knowledge concerning these enzymes, their roles in cancer, and their potential as targets in future cancer therapies.

Targeting Heme for the Identification of Cytotoxic Agents by Shiming Zhang, Hui Chen, Jessica Webster, Glenn S. Gerhard (515-522).
Certain tumor types have an increased capacity for heme synthesis, which serves as the basis for photodynamic therapy. Heme also serves as the target for the anti-malaria drug artemisinin, which has also been used as an anti-cancer drug. We developed a highthroughput screening assay to identify heme interacting (HI) compounds, which included imidazole, pyridine, carbonitrile, isocyanide, and quinoline core structures that are known to interact with heme or hemin. The cytotoxicity of several of the compounds towards human leukemia cell lines could be modulated by increasing or decreasing heme synthesis. Spectral analysis indicated that distinct molecular interactions occurred with heme, suggesting that HI compounds appear to target heme with exquisite specificity. These studies suggest that heme may serve as a novel therapeutic target for cancer drug discovery.

Human Skin-Derived Fibroblasts Acquire In Vitro Anti-Tumor Potential after Priming with Paclitaxel by Augusto Pessina, Valentina Cocce, Arianna Bonomi, Loredana Cavicchini, Francesca Sisto, Maura Ferrari, Emilio Ciusani, Stefania Navone, Giovanni Marfia, Eugenio Parati, Giulio Alessandri (523-530).
The main goal in cancer chemotherapy is to drive the drug into the tumor microenvironment to kill as many cancer cells as possible while producing the lowest collateral toxicity. Previously, we have shown that human bone marrow derived mesenchymal stromal cells (hBM-MSCs) exposed to Paclitaxel (PTX) were able to uptake and subsequently release the drug in the culture medium. PTX primed hBM-MSCs (hBM-MSCsPTX) located in the vicinity of cancer cells produced a strong inhibition of tumor cell growth both in vitro and in vivo. To expand these observations, in the present study we exposed human skin derived fibroblasts (hSDFs) to 2,000 ng/ml of PTX and then tested both cells and their conditioned medium (CM) in vitro for their capacity to inhibit the proliferation of human tumor cell lines (MOLT-4, DU-145, U87-MG, SH-SY5Y(+) and LAN-5). We found that hSDFs primed with PTX (hSDFsPTX) were able to uptake and subsequently release PTX in a time dependent manner. hSDFsPTX-derived CM(hSDFsPTX-CM) from 1:4 to 1:10 dilutions produced a significant (p<0.05) in vitro tumor growth inhibition. hSDFsPTX co-cultured with leukemia cells at 1:1 to 1:10 ratio, completely inhibited cells growth whereas no inhibition was induced by normal hSDFs cells. Our results demonstrate for the first time that hSDFs can be loaded in vitro with PTX and thus can acquire a potent anti-tumor activity. Since hSDFs can be easily isolated from skin biopsies without any particular pain and discomfort to donor patients, we conclude that hSDFs may represent a valid cell type option for carrying and delivering anti-cancer drugs.