Anti-Cancer Agents in Medicinal Chemistry (v.15, #6)

Meet Our Editorial Board Member by Alexander Shtil (673-673).

Alternative Splicing, DNA Damage and Modulating Drugs in Radiation Therapy for Cancer by Jen-Yang Tang, Ruei-Nian Li, Ping-Ho Chen, Hurng-Wern Huang, Ming-Feng Hou, Hsueh-Wei Chang (674-680).
Radiotherapy effectively destroys cancer cells in many sites of the body, but several limitations remain. This study investigated alternative splicing, which is a common mechanism of increased diversity in mRNAs and proteins. The relationships of alternative splicing to DNA damage and radiation such as UV and ionizing radiation were analyzed. The DNA damage responses of many genes involved in alternative splicing were compared between non-radiation and radiation treatments. Drugs that affect radioresistence or radiosensitization by modulating the effects of alternative splicing and radiation were also reviewed.

Effects of Plants and Isolates of Celastraceae Family on Cancer Pathways by Syed Nasir Abbas Bukhari, Ibrahim Jantan, Mohamed Ali Seyed (681-693).
The evaluation of crude drugs of natural origin as sources of new effective anticancer agents continues to be important due to the lack of effective anticancer drugs currently used in practice which are generally accompanied with adverse effects at different levels of severity. The aim of this concise review is to gather existing literature on anticancer potential of extracts and compounds isolated from Celastraceae species. This review covers six genera (Maytenus, Tripterygium, Hippocratea, Gymnosporia, Celastrus and Austroplenckia) belonging to this family and their 33 isolates. Studies carried out by using different cell lines have shown remarkable indication of anticancer activity, however, only a restricted number of studies have been reported using in vivo tumor models. Some of the compounds, such as triptolide, celastrol and demethylzeylasteral from T. wilfordii, have been extensively studied on their mechanisms of action due to their potent activity on various cancer cell lines. Such promising lead compounds should generate considerable interest among scientists to improve their therapeutic potential with fewer side effects by molecular modification.

MicroRNAs and Targeted Therapies in Non-small Cell Lung Cancer: Minireview by Carmelo Tibaldi, Armida D'Incecco, Alessandro Lagana (694-700).
The discovery of driver oncogene alterations in non-small cell lung cancer (NSCLC), such as EGFR, EML4-ALK, MET and RAS, as well as the identification of their specific targeted inhibitors have led to new opportunities for treatment of this tumor.
Drug resistance, intrinsic or acquired, represents the major cause of failure of novel biological agents.
MicroRNAs (miRNAs) are a family of small non-coding RNAs that can silence their cognate target genes by specifically binding mRNAs or inhibiting their translation. The recent evidences that several micro-RNAs can modulate the oncogenic driver pathways in NSCLC and that they are involved in drug resistance of their targeted inhibitors, have paved the way for new therapeutic strategies.
This minireview aims 1) to explore the potential mechanisms by which key miRNAs may up-regulate or down-regulate specific oncogenic driver pathways; 2) highlight the role of microRNAs in the mechanisms of resistance to targeted therapies; 3) discuss the therapeutic potential by using short-interfering RNAs or artificial miRNAs as anti-cancer therapies.

Molecular Treatment of Different Breast Cancers by Yanfang Wang, Shousong Cao, Yihui Chen (701-720).
Breast cancer is subdivided into three types: hormone (estrogen and progesterone) receptor (ER and PR) positive, Her2-neu positive and triple negative breast cancers. In general, surgical and radiation treatments are similar, but drug treatment for different subtypes of breast cancers is different. Endocrine therapy (ET) is specifically used for the treatment of ER and PR positive breast cancers. This review discusses every aspect of endocrine therapy: ovarian suppression agents, selective estrogen receptor modulators (SERMs) and downregulators, and aromatase inhibitors (AIs). The most famous agents for the treatment of HER2 positive breast cancers are trastuzumab and its derivative Kadcyla (ado-trastuzumabemtansine). Other agents for the treatment of this subtype of breast cancers are also discussed. For the treatment of triple-negative breast cancers (TNBC) and other breast cancers, the following agents are discussed: anthracyclines and related regimens, taxanes, combination therapy of platinum with taxanes, combination therapy to counter drug resistance, ixabepilone and other epothilones, angiogenesis inhibitors. The lack of known specific molecular targets has promoted abundant research in order to find possible 'vulnerabilities' in TNBC. For the first time, we propose thetranslocator protein (TSPO) 18 kDa as a potential target for TNBC. Furthermore, currently Photodynamic Therapy (PDT) is way under-explored for the treatment of breast cancers. In this review, PDT for the treatment of breast cancers is discussed. We also discuss imaging-guided therapy for breast cancers. Finally, from a perspective point of view, we call on the development of more potent agents for differentiation therapy.

The Use of Anthracyclines for Therapy of CNS Tumors by Martina da Ros, Anna Lisa Iorio, Maurizio Lucchesi, Alessia Stival, Maurizio de Martino, Iacopo Sardi (721-727).
Despite being long lived, anthracyclines remain the 'evergreen' drugs in clinical practice of oncology, showing a potent effect in inhibiting cell growth in many types of tumors, including brain neoplasms. Unfortunately, they suffer from a poor penetration into the brain when intravenously administered due to multidrug resistance mechanism, which hampers their delivery across the blood brain barrier.
In this paper, we summarize the current literature on the role of anthracyclines in cancer therapy and highlight recent efforts on 1) development of tumor cell resistance to anthracyclines and 2) the new approaches to brain drug delivery across the blood brain barrier.


Apigenin and Breast Cancers: From Chemistry to Medicine by Seyed Mohammad Nabavi, Solomon Habtemariam, Maria Daglia, Seyed Fazel Nabavi (728-735).
Breast cancer is one of the most common causes of the death among women worldwide. Metabolic disorders, alcohol consumption, hormone replacement therapy, genetic susceptibility and not having children are well known risk factors for breast cancer. Surgical resection, radiation therapy, and chemotherapy are among the limited treatment options for breast cancer. Thus, there is growing need to find new chemopreventive agents that may be effective in prevention and/or management of breast cancer. Natural products such as flavonoids provide a variety of anticancer compounds which can be useful for prevention or treatment of breast cancer. The usefulness of dietary phytochemicals in the prevention of this disease is supported by a plethora of experimental and epidemiological studies. Apigenin, a well-known flavone, is found in several dietary plant foods such as parsley, celery, thyme, celeriac, chamomile, onions, lemon balm, and oranges. Extensive studies have shown that apigenin have potent antioxidant, anti-inflammatory, and anticarcinogenic properties. The aim of the present communication is to establish the therapeutic potential of apigenin against breast cancer through critical analysis of data from 5 in vitro and in vivo studies. We also review the molecular mechanisms underlying the anticancer effects, natural sources, bioavailability, as well as the chemistry of apigenin.

Anti-resorptive Drugs and their Impact on Maxillofacial Bone among Cancer Patients by Farzad Borumandi, Tara Aghaloo, Luke Cascarini, Alexander Gaggl, Kunmi Fasanmade (736-743).
This article aims to give an overview on etiology, diagnosis and treatment options of osteonecrosis of the jaw bone among cancer patients receiving anti-resorptive drugs (ARDs). The physiologic bone function of continuous resorption and buildup is modified by the use of ARDs. Although ARDs proved to reduce pain and to improve the quality of life in patients with metastasizing bone disease, side effects such as medication related osteonecrosis of jaw bone (MRONJ) have been frequently reported since ARDs were firstly introduced. The new generation of ARDs such as Denosumab is associated with the same incidence of MRONJ among cancer patients. The etiology of MRONJ is not entirely understood and many hypotheses have been proposed. ARDs can modify the hard tissues directly by accumulation in the bone, or indirectly by suppression of the osteoclasts, inhibition of angiogenesis and vascularity. Some ARDs such as Bisphosphonates have reportedly the capacity to interfere directly and indirectly with the bone physiology. MRONJ can be a debilitating disease with non healing freely exposed bone in the oral cavity in patients, who already suffer from a primary cancerous disease. Knowledge of MRONJ as a potential side effect of ARDs is crucial for health professionals treating patients with bone modulating drugs.

5-Benzylidene-3,4-dihalo-furan-2-one derivatives inhibit human leukemia cancer cells through suppression of NF-κB and GSK-3β by Fang Wang, Jing Lin, Wen Hou, Mei-Yan Huang, Ping-Hua Sun, Wei-Min Chen (744-754).
It has been demonstrated that PPARγ agonists effectively inhibit proliferation, metastasis as well as induce apoptosis in human cancer cell lines. In this study, twenty-two rosiglitazone analogues, 5-benzylidene-3,4- dihalo-furan-2-one derivatives, which have been identified as PPARγ agonists in our previous work, were evaluated for their antitumor effects. Among these compounds, (Z)-3,4-dibromo-5-(3-methoxy-4-((3,5,6-trimethylpyrazin-2- yl)methoxy)benzylidene)furan-2(5H)-one (6w) shows the best antitumor activity, especially against the leukemia cell line U937, resulting in significant cytotoxicity, increased apoptosis and changes in mitochondrial membrane potential. Up-regulation of pro-apoptosis-associated proteins (Bax, caspase-3 and caspase-9) and cleaved PARP as well as down-regulation of anti-apoptosis protein Bcl-2 are observed in 6w-treated U937 cells. It was shown that the antitumor effect of 6w stems from its ability to inhibit the PPARγ-dependent expression of NF-κB and GSK-3β.

Recent evidence suggests that a small subset of cells within tumors have 'stem cell-like' characteristics. However, direct proof of the population of liver CSCs remains elusive. Further research is needed to identify cells with stem cell properties in established HCC cell lines. Our previous investigation found that tumor spheres are essentially enriched in CSCs. We hypothesized that chemoresistance in hepatocellular carcinoma (HCC) is due to enrichment of cancer stem cells via the PI3K/Akt pathway. We found that tumor spheres cells formed from HCC cells contained a high percentage of CD90+ cells, and these cells were more tumorigenic and resistant to doxorubicin (DOX), showing a higher proliferation rate and lower apoptosis rate compared to cells in monolayer culture. Treatment with DOX and PI3K/Akt inhibitor increased apoptosis and reduced viability among cells in the tumorspheres. The expression of p-Akt1 was upregulated in tumorsphere-forming cells treated with DOX but downregulated upon further treatment with the PI3K/Akt inhibitor. Our results demonstrate that HCC cells in tumorspheres with cancer stem cell properties achieve chemoresistance via the PI3K/Akt1 pathway.

Ligustrazine Suppresses the Growth of HRPC Cells through the Inhibition of Cap- Dependent Translation Via Both the mTOR and the MEK/ERK Pathways by Jiaoyan Han, Jiao Song, Xiangyun Li, Ming Zhu, Wei Guo, Wei Xing, Rongshen Zhao, Xiao He, Xiaoping Liu, Shali Wang, Yunyun Li, Hong Huang, Xiang Xu (764-772).
Ligustrazine (TMP) has recently been used for the treatment of various cancers. However, its exact mechanisms of action, particularly the functions and the mechanisms of Ligustrazine in human hormone-refractory prostate cancer (HRPC), have not yet been extensively studied. Recently, our findings suggest that Ligustrazine dose- and time-dependently inhibits the growth of HRPC cells by reducing their proliferation and promoting apoptosis. Interestingly, the treatment of hormone-refractory prostate cancer (PC-3) cells with Ligustrazine results in a significant inhibition of the activation of mTOR and related downstream targets, which are critical for cell growth. Furthermore, pull-down assays with 7-methyl- GTP Sepharose 4B beads indicate that Ligustrazine reduces the available eIF4E for translation initiation. Accordingly, the results from the translation assay using a luciferase reporter system further demonstrate that Ligustrazine indeed inhibits cap-dependent translation. In addition, the transient overexpression of eIF4E or MNK1 prevents the Ligustrazine-induced inhibition of proliferation and confers significant protection against Ligustrazine-induced apoptosis. Therefore, the present study provides evidences that Ligustrazine may be a candidate for therapeutic reagent for the treatment of HRPC and certifies that Ligustrazine modulates the availability of eIF4E mainly through the mTOR and MEK/ERK signaling pathways to inhibit cap-dependent translation. Taken together, our results indicate that the inhibition of cap-dependent translation is likely an essential mechanism in Ligustrazine-induced apoptosis.

In Vivo Anticancer Activity, Toxicology and Histopathological Studies of the Thiolate Gold(I) Complex [Au(Spyrimidine)(PTA-CH2Ph)]Br by Elena Garcia-Moreno, Sonia Gascon, Jose A. Garcia de Jalon, Eduardo Romanos, M Jesus Rodriguez-Yoldi, Elena Cerrada, Mariano Laguna (773-782).
A physiologically stable thiolate gold(I) derivative [Au(Spyrimidine)(PTA-CH2Ph)]Br has shown inhibition in colon cancer proliferation of Caco-2/TC7, Caco-2/PD7 and HTC-116-luc2 cell lines via apoptotic pathway and S-phase arrest in the cell cycle. Intraperitoneal injection of [Au(Spyrimidine)(PTA-CH2Ph)]Br in athymic nude mice inoculated with HTC-116-luc2 cells prolonged their survival and greatly inhibited tumour growth, near to disappearance. Low concentration of gold in urine and blood were detected in mice after 48 h of administration of 5 mg/kg body weight (bw) of the gold complex and non-organ (kidney and liver) damage has been detected after gold treatment. The results obtained suggested that the thiolate gold(I) derivative shown here could be considered as a candidate for therapeutic treatment in colon cancer.

The new complex of {[Co(4,4′-Bipy)(H2O)4]·(Pyri)·3H2O}n (4,4′-Bipy = 4,4′-bipyridyl, H2Pyri = 3,5- Pyridinedicarboxylic acid) was synthesized and characterized by IR, element analysis and X-ray single-crystal diffraction. The binding of the complex with extracted HeLa cells DNA was investigated by UV and fluorescence spectrum. Gel electrophoresis assay demonstrated the ability of the complex cleaving the extracted HC-DNA. The complex exhibited a higher cytotoxicity against tumor cells in vitro. Furthermore, the apoptotic tests indicated the complex had an apoptotic effect on HeLa cells.

4,6-diaryl Pyrimidones as Constrained Chalcone Analogues: Design, Synthesis and Evaluation as Antiproliferative Agents by Dinesh Kumar, Kunal Nepali, PMS Bedi, Suresh Kumar, Fayaz Malik, Subheet Jain (793-803).
4,6-diarylpyrimidones as constrained chalcone analogues have been synthesised in the present study. The synthesised compounds were evaluated against a panel of human cancer cell lines. Striking selectivity was displayed by the compounds against MiaPaCa (Pancreatic) cell lines while PC-3 (prostate) and A-549 (lung) cell lines were almost resistant to the exposure of the test compounds. Compound SK – 25 exhibited remarkable cytotoxicity against MiaPaca-2 cell line with an IC50 value of 1.95 µM and was found to induce apoptosis evidenced through phase contrast microscopy, DAPI staining and mitochondrial membrane potential loss. The cell phase distribution studies indicated that the apoptotic population increased from 1.79% in control sample to 30.33 % in sample treated with 20 µM compound SK-25.