Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 15, Issue 1, 2015

The Breast Cancer 1 protein (BRCA1) is a tumor suppressor involved in basic cellular functions necessary for cell replication and DNA synthesis, but reduced expression of BRCA1, due to mutations or epigenetic inactivation, leads to impaired mammary gland differentiation and increased risk of breast cancer development. Although BRCA1 acts as a tumor suppressor and is present in all cells, where it is essential for the maintenance of the genome integrity, it is still not clear why mutations in the BRCA1 gene predispose to breast and ovarian, but not to other types of cancer. In the first part of this review, we briefly discuss the function and regulation of the BRCA1 protein, including its role associated with familial and sporadic breast cancer. The second part is an overview of the therapeutic compounds used for breast cancer treatment targeting BRCA1, and the natural food components that hold potential preventive effect against those types of breast cancer in which BRCA1 expression is either reduced or lacking. Further studies elucidating the interactions between dietary compounds and cellular pathways, involved in regulation of BRCA1expression, are necessary for the development of strategies that may successfully prevent or treat breast cancer.

Neoadjuvant therapy for triple negative breast cancer (TNBC) has recently generated growing interest given the more aggressive biologic characteristics of such subtype and the lack of approved targeted therapies. Systemic chemotherapy represents the mainstay of treatment for TNBC. Although neoadjuvant chemotherapy has consistently demonstrated higher response rates for TNBC compared to non-TNBC, and the pathological complete response predicts long-term outcome, most patient display residual disease with a higher risk of relapse. In order to improve the outcome of TNBC new chemotherapic combinations, including platinum agents, and different targeted agents such as antiangiogenetics, poly-ADP ribose polymerase (PARP) inhibitors and other small molecule inhibitors are being evaluated in neoadjuvant setting. Currently, the research is ongoing to further characterize TNBC from a phenotypical and molecular perspective, in order to identify potential new target agents and to individualize the treatment. In this regard, the neoadjuvant setting may represent the best potential scenario to assess the activity and the sensitivity of novel agents.

The leaves of Camellia sinensis (L.) are the source of tea, the second most consumed beverage worldwide. Tea contains several chemical compounds such as polyphenols (mainly catechins), caffeine, theophylline, L-theanine, among many others. Polyphenolic compounds are mainly responsible for its significant antioxidant properties and anticarcinogenic potential. Bladder cancer is one of the most common types of cancer, and its progression and onset are thought to be controlled by dietary and lifestyle factors. Epidemiological studies showed that the regular consumption of tea can be a preventive factor for this type of cancer, and several in vivo and in vitro studies reported that tea and its components may interfere in the cancer cells’ signaling, preventing the bladder tumor progression. The mechanisms responsible for this protection include deregulation of cell cycle, induction of apoptosis while protecting the surrounding healthy bladder cells, inhibition of metastization processes, among others. Herein, we discuss the potential beneficial effects of tea and tea components in bladder cancer prevention and/or treatment, and how they can be helpful in finding new therapeutic strategies to treat this type of cancer.

The process of angiogenesis involves the formation of new blood vessels from pre-existing vasculature by the over expression of certain factors leading to the growth and development of all solid tumor types. Hepatocyte growth factor receptor abbreviated as c-Met and vascular endothelial growth factor abbreviated as VEGF are some of the factors responsible for the induction in tumor growth and development. Recently a number of analogues associated with these receptors are under study. US FDA on November 29, 2012 approved a drug named cabozantinib formerly known as XL184 which is being marketed under the trade name of Cometriq for the treatment of Medullary Thyroid Cancer (MTC). Designing of the drug has been done in such a fashion that it can inhibit both VEGFR2 and c-Met simultaneously without over expressing any of the factors leading to the inhibition of angiogenesis. The drug is still under study for the evaluation of its efficacy in cases of many other solid tumor types including breast cancer, castration resistant prostate cancer (CRPC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastric or gastroesophageal junction cancer, melanoma, small cell lung cancer (SCLC), ovarian cancer and primary peritoneal or fallopian tube carcinoma. This review article consists of preclinical and clinical data of cabozantinib and its efficacy and safety towards various types of solid tumors.

Recent statistics revealed that cancer is one among the main reasons for death throughout the world. Several treatments are available but still there is no cure when it is detected at late stages. One of the treatment modes for cancer is chemotherapy which utilizes anticancer drugs in order to eradicate the cancer cells by apoptosis. Apoptosis is a programmed cell death through which body maintains homeostasis or kills cancer cells by utilizing its cell machinery. Recent researches have concluded that dietary agents have a putative role in instituting apoptosis of cancer cells. Honey, one of the victuals rich in antioxidants, has a long-standing exposure to humans and its role in cancer prevention and treatment is a topic of current interest. Various researchers have been experimenting honey against different cancers and provided valuable insights about the apoptosis induced by the honey. This review will highlight the recent findings of apoptotic mechanism involved in different cancer cells. Further it also reports antitumor activity of honey in some animal models. Hence it is high-time to initiate more preclinical trials as well as clinical experiments which would further add to the knowledge of anticancer nature of honey and also endorse honey as a potential candidate in the war against cancer.

Cancer is a serious global health issue. Cancer of the cervix is one of the leading gynecological malignancies worldwide; though it is more prevalent in the developing countries. Fruitful approaches are needed to control cervical cancer. Awareness through proper education, screening and early detection may pave a way to combat the disease process in the first place. Surgery, chemotherapy and radiotherapy are some of the common modes of treatment for cervical cancer. Conventional medical treatments often are not able to eliminate the offending growth fully and are not free from complications. Side effects very often are disastrous. Therefore, it is high time to focus our attention to bring about a novel way to tackle the problem. Advocating holistic approach using plant derived phytochemicals may address this health problem. These molecules show potent anticancer potential and are free from toxicity. Adjunctive therapies using phytochemicals may prove to be of tremendous importance. Plants are a prime source of effective drugs for the treatment of various forms of cancer. Many of these compounds are well characterized and have led the researchers to develop potential chemotherapeutic agents. Neutraceuticals may not replace the conventional treatment regimen, but they may enhance the efficacy of chemotherapy and radiotherapy.

Berberine exerted anti-cancer effect in various cancer cell lines, and was also implied in the treatment of metabolic related diseases. Given the metabolic modulation, we hypothesized that berberine possessed anti-cancer effect under the assistance of metabolic interference. Working as a modulator, metabolic enzyme inhibitor or complex network regulator in energy metabolism, berberine was highlighted in current cancer research. A reasonable cross talk between Chinese medicine and energy homeostasis provided a solid foundation for berberine interference on cancer cells reprogramming metabolism. Our result showed that berberine regulated the reprogramming metabolism through three aspects simultaneously, including mitochondrial oxidative phosphorylation, glycolysis and macromolecular synthesis. This interference with reprogramming metabolism was a continuous, simultaneous and sustainable approach in a moderate mode. And it could be regarded as a gentle and virtuous cycle from a multi-level perspective, indicating an integrated approach in cancer therapy. Meanwhile, we thought that Chinese medicine could link cancer and metabolic related diseases from a dynamic perspective through integrated network pharmacology. This cross talk would be a realistic and significant strategy for anti-cancer drug discovery and needs further investigation in future.

The study of anticancer properties from natural products has regained popularity as natural molecules provide a high diversity of chemical structures with specific biological and medicinal activity. Based on a documented library of the most common medicinal plants used by the indigenous people of North America, we screened and isolated compounds with anti-breast cancer properties from Juniperus communis (common Juniper). Using bioassay-guided fractionation of a crude plant extract, we identified the diterpene isocupressic acid and the aryltetralin lignan deoxypodophyllotoxin (DPT) as potent inducers of caspase-dependent programmed cell death (apoptosis) in malignant MB231 breast cancer cells. Further elucidation revealed that DPT, in contrast to isocupressic acid, also concomitantly inhibited cell survival pathways mediated by the MAPK/ERK and NFΚB signaling pathways within hours of treatment. Our findings emphasize the potential and importance of natural product screening for new chemical entities with novel anticancer activities. Natural products research complemented with the wealth of information available through the ethnobotanical and ethnopharmacological knowledge of the indigenous peoples of North America can provide new candidate entities with desirable bioactivities to develop new cancer therapies.

To search for novel anticancer agents, we designed and synthesized a series of new triazolyl berberine derivatives. The evaluation of all the synthesized compounds and their anticancer activities against a panel of four human cancer cell lines including MCF-7 (breast), MCF-7/ADR (breast), SW-1990 (pancreatic), SMMC-7721 (liver) and the noncancer cell line HUVEC (human umbilical vein endothelial cell). The results showed that most of the compounds displayed better anticancer activities against MCF-7 and SMMC-7721 compared with berberine. Among these derivatives, compounds 5p and 5a exhibited the most potent inhibitory activities against the SMMC-7721 and SW-1990 cell lines with IC50 values of 14.861 ± 2.4 μM and 16.798 ± 3.4 μM. Furthermore, compounds 5p, 5a and 5n exhibited much better selectivity toward the normal cell line HUVEC than berberine.

The most common solid tumor is testicular cancer among young men. Bleomycin is an antitumor antibiotic used for the therapy of testicular cancer. TRAIL is a proapoptotic cytokine that qualified as an apoptosis inducer in cancer cells. Killing cancer cells selectively via apoptosis induction is an encouraging therapeutic strategy in clinical settings. Combination of TRAIL with chemotherapeutics has been reported to enhance TRAIL-mediated apoptosis of different kinds of cancer cell lines. The molecular ground for sensitization of tumour cells to TRAIL by chemotherapeutics might involve upregulation of TRAIL-R1 (TR/1, DR4) and/or TRAIL-R2 (TR/2, DR5) receptors or activation of proapoptotic proteins including caspases. The curative potential of TRAIL to eradicate cancer cells selectively in testicular cancer has not been studied before. In this study, we investigated apoptotic effects of bleomycin, TRAIL, and their combined application in NTera-2 and NCCIT testicular cancer cell lines. We measured caspase 3 levels as an apoptosis indicator, and TRAIL receptor expressions using flow cytometry. Both NTera-2 and NCCIT cells were fairly resistant to TRAIL’s apoptotic effect. Incubation of bleomycin alone caused a significant increase in caspase 3 activity in NCCIT. Combined incubation with bleomycin and TRAIL lead to elevated caspase 3 activity in Ntera-2. Exposure to 72 h of bleomycin increased TR/1, TR/2, and TR/3 cell-surface expressions in NTera-2. Elevation in TR/1 cell-surface expression was evident only at 24 h of bleomycin application in NCCIT. It can be concluded that TRAIL death receptor expressions in particular are increased in testicular cancer cells via bleomycin treatment, and TRAIL-induced apoptosis is initiated.

This study describes anticancer activity and DNA binding properties of two cyclometalated platinum (II) complexes with non-leaving lipophilic ligands; deprotonated 2-phenylpryidine (ppy): C1 and deprotonated benzo[h] quinolone (bhq): C2. Both complexes demonstrate significant anticancer activity and were capable to stimulate Caspase-III activity in Jurkat cancer cells. The results of Acridine orange/Ethidium bromide(AO/EtB), along with those of Caspase-III activity suggest that these complexes can induce apoptosis in the cancer cells. Moreover, C1 with flexible chemical structure indicates considerably higher anticancer activity than C2 which possesses a higher structural rigidity. Additionally, C2 represents a complex which is in part inducing cancer cell death due to the cell injury (necrosis). The absorption spectra of DNA demonstrate a hypochromic effect in the presence of increasing concentration of these complexes, reflecting DNA structural alteration after drug binding. Also, EtB competition assay and docking results revealed partial intercalation and DNA groove binding for the metal complexes. Overall, from the therapeutic point of view, ppy containing platinum complex (C1) is a favored anticancer agent, because it induces signaling cell death (apoptosis) in cancer cells, and lacks the necrotic effect.

A series of seven derivatives of 1,1'-(5,6-dimethoxy-3-methyl-1-benzofuran-2,7-diyl)diethanone was synthesized and characterized by 1HNMR and ESI MS spectra and elemental analyses. The obtained new compounds and three halogen derivatives of benzofuran, reported in our earlier work, were tested for their cytotoxic properties in human chronic (K562) and acute (HL60) leukemia cells, human cervical cancer (HeLa), and normal endothelial cells (HUVEC). Four compounds (2, 3, 4, 5), which contain halogens in their structure showed significant anticancer activity. The most promising was 1,1'-[3- (bromomethyl)-5,6-dimethoxy-1-benzofuran-2,7-diyl]diethanone (2), which was highly and selectively toxic for K562 cells (IC50 of 5μM) and HL60 cells (IC50 of 0.1μM), which showed no cytotoxicity toward HeLa and HUVEC cells. Moreover, the observed remarkable cytotoxicity of this compound toward K562 cells resulted from cells apoptosis.

Several radiolabeled alpha-melanocyte stimulating hormone (α-MSH) analogs have been studied for their abilities to target melanoma tumor cells through specific recognition and binding to the melanocortin receptor 1 (MCR1). In this work, a lactam bridgecyclized α-MSH analog was labeled with 99m via the hydrazinonicotinamide (HYNIC) chelator and characterized for its melanoma tumor targeting properties. The bifunctional chelating agent HYNIC-Boc was attached to the N-terminus of the MSH peptide followed by the lactam cyclization, resulting in the HYNIC-cyc-MSH analog. The lactam cyclized peptide displayed high affinity and specificity for MC1-receptors present on B16/F1 melanoma tumor cells, exhibiting an IC50 of 6.48 nM. HYNIC-cyc-MSH was radiolabeled with 99mTc using two common co-ligands, tricine and EDDA. In vitro, the radiochemical stability, cell binding and efflux properties were similar between the peptides radiolabeled with tricine and EDDA as co-ligands. In vivo, biodistribution studies (n=4) demonstrated that 99mTc- HYNIC-cyc-MSH/tricine had superior tumor to muscle and tumor to blood ratios than 99mTc-HYNIC-cyc-MSH/EDDA at early time points. Planar gamma imaging of melanoma bearing mice showed that 99mTc-HYNIC-cyc-MSH/tricine was able to clearly visualize tumors, underscoring the potential utility of 99mTc labeled lactam cyclized MSH molecules as melanoma imaging agents.

14 new structures of isoxazole-moiety-containing quinazoline derivatives(3a~3n) were synthesized for the first time and characterized by IR, 1H NMR, 13C NMR, ESI-MS. Subsequently, their in vitro anticancer activity against A549, HCT116 and MCF-7 cell lines was preliminarily evaluated using the MTT method. Among them, most compounds showed good to excellent anticancer activity, especially 3d, 3i, 3k and 3m exhibited the more potent anticancer activity against A549, HCT116 and MCF-7 cell lines, which can be regarded as the promising drug candidates for development of anticancer drugs.