Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 18, Issue 7, 2018

Objective: Multiparametric Magnetic Resonance Imaging (mpMRI) has become a very useful tool in the management of PCa. Particularly, there is a great interest in using mpMRI for men on Active Surveillance (AS) for low risk PCa. The aim of this systematic review was to critically review the latest literature concerning the role of mpMRI in this clinical setting, underlying current strengths and weakness. Evidence Acquisition: A comprehensive literature research for English-language original and review articles was carried out using the National Center for Biotechnology Information PubMed database with the aim to identify studies pertaining to mpMRI for AS in low risk PCa patients. The following search terms were used: active surveillance, prostate cancer and multiparametric magnetic resonance imaging. Evidence Synthesis: Data from 28 recent original studies and reviews were reviewed. We only considered studies on the use of mpMRI in selecting AS patients and during AS follow-up, in order to solve two important questions: -Can mpMRI have a role in improving the detection of clinically significant disease, better selecting AS patients? -Can mpMRI identify the progression of disease and, consequently, be used during AS follow-up? Conclusions: mpMRI is useful to better select the ideal candidates to AS and to monitor them during follow-up. However, despite many advantages, there are yet important limitations to detect all clinically significant PCa and to better define mpMRI-radiological progression during AS. Further larger prospective studies are needed to definitively solve these important problems.

The incidentally discovered, clinically-localized, small renal mass (clinical stage T1aN0M0, ≤4cm) is the most commonly diagnosed entity in Renal Cell Carcinoma (RCC) – now accounting for at least 40% of newly diagnosed renal tumors. Given the above argument, Active Surveillance (AS) has emerged as a viable management strategy for SRM. This review will examine and discuss the existing literature regarding selection criteria for AS. AS of clinical T1a renal masses is emerging as a safe and effective management strategy in selected patients, yet appropriate patient selection and counseling remains an area of great interest. Long-term clinical outcomes are just beginning to be reported, thus much of the supporting evidence on AS and patient selection is based on retrospective data of heterogeneous quality. Nevertheless, there are certain conclusions that can be drawn, despite these current limitations. Appropriate selection of candidates should include a comprehensive evaluation of competing health risks, tumor characteristics, and patient preferences.

Despite the rise of small renal tumour (SRMs) diagnosis and related surgeries, death rate of kidney cancer is increasing, suggesting a non-optimal management of SRMs. Active Surveillance (AS) for kidney cancer was introduced to deal with this paradox. However, incertitude remains on whether and when AS can replace surgery in selected patients. We performed a literature search, reviewed and discussed the evidence in favour of AS or surgery for SRMs. Histopathology and natural history of SRMs, including the percentage of benign tumours amongst SRMs, tumour growth rate, life expectancy of SRMs patients being generally older, and current results of AS series seem to support its use in selected groups. However, kidney cancer is a heterogeneous entity, metastasis and ≥T3a status can be found also for SRMs and no biomarkers or other parameters are available to identify lethal SRMs. Despite the recent improvement in the diagnostic and prognostic work through imaging modalities, renal biopsies and nomograms, the interpretation of a survival plot subjectively is still not possible. The majority of AS studies are retrospective and extensive level 1 evidence cohorts with long term follow up are lacking. No unanimity is present regarding inclusion and exclusion criteria to undergo AS, follow up timings and AS exit criteria. Surgery is the only definitive treatment and remains the current standard. A better understanding of kidney cancer biology and SRMs behaviour is needed to clarify the role of AS and its indications.

Background: A recent surge in biomarkers to aid management of men with prostate cancer has occurred. Their applications are varied and not all tests are applicable to the active surveillance setting. Objective: To review primary evidence on genetic and immunohistochemical biomarkers, and their role on patient selection and risk stratification for men on active surveillance for prostate cancer. Evidence Acquisition: A PubMed electronic search using the terms (biomarker or genetic or histopathological) AND ("prostate cancer" AND "active surveillance") was performed from inception to April 2015. Evidence Synthesis: Of the biomarkers reviewed, Prostate Health Index (PHI) and Oncotype DX Genomic Prostate Score (GPS), were identified to currently hold greatest potential benefit to aid risk stratification of men for AS. Higher PHI, at baseline and during follow-up, was shown to predict pathological upgrading at rebiopsy at two single institutions, but with small cohorts (n<200). The Oncotype DX GPS test has been validated on men suitable for AS but having upfront radical prostatectomy. Increase in GPS was shown to predict upgrading and upstaging at radical prostatectomy and biochemical recurrence post radical prostatectomy. Prospective validation in AS cohorts is yet to be performed. Conclusions: PHI and Oncotype DX GPS show promise in aiding risk stratification for men on AS. However, larger prospective studies in AS cohorts are needed. Integration of biomarkers with existing clinical and imaging models remains a challenge.

Background: Active Surveillance (AS) is a therapeutic strategy for early-stage Prostate Cancer (PCa) conceived to balance early detection of aggressive disease and overtreatment of indolent tumor. Several active surveillance protocols have been published over the years, however the risk of misclassification still exist. In this review, we revised the current criteria of AS and evaluated the characteristics of potential risk factors of misclassification or deferred treatment. Methods: We did a systematic search of the MEDLINE database, from 1993 to May 2015, according to Preferred Reporting Items for Systematic Reviews and Meta-analysis statement guidelines and limited to the English language. The search terms used included “prostate cancer” and “active surveillance” and “criteria. We have excluded from the study reviews and editorial comments as well as multiple papers from the same data sets. Results: Although the follow-up of reported studies was a quite short compared to the duration of the disease, the data are sufficient to conclude that active surveillance should be offered to men with low-risk disease and to men with intermediate risk and poor life expectancy. The present challenge, in fact, is to differentiate the clinically silent disease from the unfavorable course by identifying the right timing for any deferred treatment. This is made particularly difficult by the absence of randomized controlled trials directly comparing different AS monitoring methods. Conclusion: As summarized in this review, it is still difficult to select patients eligible for active surveillance and differentiate them from those that should move to active treatment. From the data, currently available in the literature, however, it is possible to recommend active surveillance to men with low-risk disease and to men with intermediate-risk disease but with short life expectancy.

Background: The prevalence of lung cancer is 14% among the newly diagnosed cancer cases worldwide. Currently, the number of drugs that are in clinical practice is having a high prevalence of side effect and multidrug resistance. Researchers have made an attempt to expand a suitable anticancer drug that has no MDR and side effect. Objective: Extensive exploration of Coumarin derivatives as a potent inhibitor of variety of proteins including EGFR, tyrosine kinase, ERK1/2, PI3K, HSP 90, Bax, STAT proteins, NF-ΚB and telomerase which have been associated with lung cancer. Method: The recent literature was surveyed utilizing the online resources and databases including scifinder, pubchem, EMBL, scopus and google scholar. Results: Upon analyzing the structure-activity relationship, it was found that N-aryl carboxamide, phenyl substitution at the C-3 position and 1,2,3- triazolyl, trihydroxystilbene, amino substitution at the C-4 position of the coumarin nucleus were the most effective in targeting lung cancer. Conclusion: This review is a collaborative and extensive compilation of synthetic strategies, mechanism of action, and the structure-activity relationship thereof for the management of lung carcinoma.

This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland secretory product, an evolutionarily highly conserved molecule; it is also an antioxidant and an impressive protector of mitochondrial bioenergetic activity. MLT is characterized by an ample range of activities, modulating the physiology and molecular biology of the cell. Its physiological functions relate principally to the interaction of G Protein-Coupled MT1 and MT2 trans-membrane receptors (GPCRs), a family of guanidine triphosphate binding proteins. MLT has been demonstrated to suppress the growth of various tumours both, in vivo and in vitro. In this review, we analyze in depth, the antioxidant activity of melatonin, aiming to illustrate the cancer treatment potential of the molecule, by limiting or reversing the changes occurring during cancer development and growth.

Methods: The synthesis of conjugates of flutamide with resorcinarene-PAMAM-dendrimers as well as alkyl and ethyl phenyl chains in the lower part of the macrocycle as a nucleus and diethylenetriamines in the dendritic branches gives the opportunity to obtain conjugates in one step of synthesis with 16 and 64 flutamide moieties in the structure. Results: The in vitro anticancer studies showed that the conjugates of flutamide are more active than the free flutamide and the flutamide derivatives, thus diminishing the amount of flutamide used. The resorcinarenedendrimer- flutamide conjugates with a high drug payload improve the activity of the drug. Conclusion: This is important in delivering a sufficient amount of flutamide and suggests that the dendrimer facilitates more of the drug being introduced into cells. It was also observed that the new conjugates are less toxic than the anti-androgens.

Background: Actinic Keratosis (AK), is the most common precancerous skin lesion induced by the excessive Ultraviolet B (UVB) and is a significant threat to the public health. UVB exposure causes oxidative DNA damage and is considered to be a significant contributor to AK and subsequent development of skin cancer. Besides, activation of p38 MAPK also plays a significant role in the development of AK. Objective: This study aimed at the development of a nature compound which can inhibit UVB-induced AK. Method: MTS Cell Proliferation Assay Kit was used to detect the toxicity of astragalin. HE-staining, Immunohistochemical, Western blot and Enzyme Linked Immunosorbent Assay were applied to examine the clinicopathologic feature of AK and the change of p38 MAPK signal pathway treated with astraglin under the condition of UVB in vitro and in vivo. Results#154;In our clinical findings revealed that p38 MAPK, phospho-MSK1, and γ -H2AX were significantly highly expressed in human AK tissue than the normal healthy skin tissue. Moreover, in vitro studies showed that UVB induced the phospho-MSK1 and γ-H2AX in a time- and dose-dependent manner in HaCaT cells. Further, in vitro kinase assay demonstrated that astragalin could directly bind to p38 MAPK and suppress p38 MAPK activity. Furthermore, astragalin exhibited no toxicity and suppressed the UVB-induced expression of phospho- MSK1 and γ -H2AX by suppressing p38 MAPK activity in a time-dependent and dose-dependent manner in HaCaT cells. The in vivo studies with animal UV model demonstrated that astragalin inhibited UVB-induced expression of phospho-MSK1 and γ-H2AX in Babl/c mice. Conclusion: These results suggested that p38 MAPK is a direct valid molecular target of astragalin for the attenuation of UVB-induced AK. Furthermore, astragalin could be a potential promising novel natural therapeutic agent for the prevention and management of UVB-induced AK with high target specificity and low toxicity.

Methods: A novel series of isoxazole (S21-S30) derivatives were designed, synthesized and screened for their anticancer activity against estrogen receptor-positive MCF-7 and negative MDA-MB-435 breast cancer cell lines. The synthesized derivative has the ability to inhibit the growth of the human breast cancer cell line at low concentrations. In vivo anticancer activity was performed on virgin female sprague dawley rats. Results: The result shows that compound S23 has more selectivity and marked estrogen modulator activity than the standard tamoxifen.

Purpose: Some aromatase inhibitors are FDA-approved agents as first-line therapy in the treatment of endocrine-responsive breast cancer. In this study, we aimed to develop new azole derivatives with higher specificity and potency. Methods: New aromatase inhibitors were designed by Molecular Operating Environment (MOE) software and synthesized in a one-step SN2 reaction. These compounds were characterized by melting point, 1H- and 13CNMR, elemental analysis and mass spectra. The in vitro and in vivo aromatase inhibition of these compounds was evaluated using the Estrone ELISA assay, and by measuring the inhibition of androstenedione-induced uterine hypertrophy. The selectivity of aromatase inhibition was investigated by the inhibition of ACTH stimulation on the plasma concentrations of aldosterone and cortisol. Results: Docking simulations showed that four new azole derivatives could efficiently interact with enzyme active sites. The in vitro aromatase-inhibition assay showed that the compounds 1,3,5-tris(imidazol-1- ylmethyl)benzene (3b) and 1,3-Bis(imidazole-1- ylmethyl) benzene (3d) effectively inhibited aromatase, with IC50 values of 0.2 nM and 6.8 nM, respectively; these values were similar to known aromatase inhibitor letrozole (IC50 0.3 nM). The in vivo aromatase-inhibitory potency of compound 3b was similar to letrozole, although compound 3b acted more selectively. Conclusion: This report introduced a new compound that can be considered as a new lead for further investigation to explore more-potent and more-selective aromatase inhibitors.

Abstract: Background: Different saponins from herbs have been used as tonic or functional foods, and for treatment of various diseases including cancers. Although clinical data has supported the function of these saponins, their underlying molecular mechanisms have not been well defined. Methods: With the simulated hypoxia created by 8 hours of Cu++ exposure and following 24 hour incubation with different concentration of saponins in HepG2 cells for MTT assay, migration and invasion assays, and for RT-PCR, and with each group of cells for immunofluorescence observation by confocal microscopy. Results#154;ZC-4 had the highest rate of inhibition of cell proliferation by MTT assay, and the highest inhibition of migration rate by in vitro scratch assay, while ZC-3 had the highest inhibition of invasion ratio by transwell assay. Under the same simulated hypoxia, the molecular mechanism of saponin function was conducted by measuring the gene expression of Hypoxia Inducible Factor (HIF)-1α through RT-PCR, in which ZC-3 showed a potent inhibition of gene HIF-1α. For the protein expression by immunofluorescence staining with confocal microscopy, HIF-1α was also inhibited by saponins, with the most potent one being ZC-4 after eight hours' relatively hypoxia incubation. Conclusion: Saponins ZC-4 and ZC-3 have the potential to reduce HepG2 cell proliferation, migration and invasion caused by hypoxia through effectively inhibiting the gene and protein expression of HIF-1α directly and as antioxidant indirectly

Background: Estrogens, as the main female steroid hormones have multiple proven effects on reproductive and non- reproductive systems. Expression of ERα and ERβ, two dominant estrogen receptors, in peripheral blood mononuclear cells in certain B-cell malignancies and the existence of estrogens receptors on mitochondria is open to question that estrogen likely has an impact on the cancerous lymphocytes life span. Acute Lymphoblastic Leukemia (ALL) is the frequent pediatric malignity which is recurrent and hardly curable in many cases. The malignant cells are generally resistant to apoptosis caused the severe lymphocytes accumulation in the peripheral blood. Methods: By focusing on mitochondria as a life/death center of the cell; in the current research we compared cytotoxicity effects of a new ferrocenyl derivative with raloxifene as well-known SERMs considering the apoptotic process and survival of cancerous lymphocytes. Results: We demonstrated that both ferrocenyl derivative and raloxifene could cause mitochondrial lesion and initiate the apoptosis process by caspase activation and cytochrome c release. Conclusion: In brief, the ferrocenyl derivative could induce estrogen-related selective apoptosis on cancerous lymphocytes by affecting mitochondrial receptors.

Background: The lack of selectivity and development of drug-resistance encourage researchers to search for novel, more efficient and multi-targeted agents with less toxicity. Objective: In this paper, a series of novel chalcone derivatives bearing diverse heterocycles have been synthesized and evaluated for their antiproliferative activity against A549 (Human Lung Adenocarcinoma) and C6 (Rat Brain Glioma) cells. Method: Structures of the title compounds (3-18) were verified by FT-IR, 1H NMR, 13C NMR, HRMS spectral data and elemental analyses. Antiproliferative activities of the compounds were evaluated using MTT assay, BrdU method, and flow cytometric analysis. Results: Compounds 9 and 15 were revealed as the most promising cytotoxic agents due to their selectivity towards A549 cells with lower IC50 values (IC50=0.05 μM and IC50=0.0316 μM) than cisplatin (IC50=0.06 μM). Flow cytometric analysis of compounds 9 and 15 showed that they affected lung cancer cells by the apoptotic pathway. Conclusion: It is concluded that this study will contribute to the research of novel antiproliferative agents.

Background: Endometrial cancer is a common cause of death in gynecological malignancies. Cisplatin is a clinically chemotherapeutic agent. However, drug-resistance is the primary cause of treatment failure. Objective: Emodin is commonly used clinically to increase the sensitivity of chemotherapeutic agents, yet whether Emodin promotes the role of Cisplatin in the treatment of endometrial cancer has not been studied. Method: CCK-8 kit was utilized to determine the growth of two endometrial cancer cell lines, Ishikawa and HEC-IB. The apoptosis level of Ishikawa and HEC-IB cells was detected by Annexin V / propidium iodide double-staining assay. ROS level was detected by DCFH-DA and NADPH oxidase expression. Expressions of drug-resistant genes were examined by real-time PCR and Western blotting. Results: Emodin combined with Cisplatin reduced cell growth and increased the apoptosis of endometrial cancer cells. Co-treatment of Emodin and Cisplatin increased chemosensitivity by inhibiting the expression of drugresistant genes through reducing the ROS levels in endometrial cancer cells. In an endometrial cancer xenograft murine model, the tumor size was reduced and animal survival time was increased by co-treatment of Emodin and Cisplatin. Conclusion: This study demonstrates that Emodin enhances the chemosensitivity of Cisplatin on endometrial cancer by inhibiting ROS-mediated expression of drug-resistance genes.

Background: Crocus sativus (Iridaceae) has been traditionally used in the Iranian folk medicine and as a culinary additive. Major components of the plant that are responsible for biological properties are saffranal, crocin, picrocrocin and crocetin. Although the level of crocetin is not high, some of the important activities of saffron such as antioxidant activity have been attributed to crocetin. Objective: In the present study, we investigated the effects of crocetin on melanogenesis in B16 melanoma cells. Methods: The effect of crocetin on intracellular and mushroom tyrosinase activity and the content of melanin was evaluated spectrophotometrically. Tyrosinase and Microphthalmia-Associated Transcription Factor (MITF) protein levels were compared between Crocetin-treated and control cells after western blot analysis. The antioxidative activity of crocetin was also investigated. Results: Crocetin could inhibit mushroom tyrosinase activity and lower the amount of melanin in B16 melanoma cells. Protein levels of tyrosinase and MITF were also decreased by crocetin. Crocetin also showed antioxidant activity and depleted cellular Reactive Oxygen Species (ROS) content but had no cytotoxicity in alamarBlue® assay. Conclusion: Taken together, decreased tyrosinase activity, melanin content, tyrosinase and MITF proteins levels, and ROS production showed the inhibition of melanogenesis in B16F10 cells by crocetin. Hence, crocetin could be suggested as a potential dermatological whitening agent in skin care products.