Exploring New Molecular Targets in Advanced Ovarian Cancer: The Aryl Hydrocarbon Receptor (AhR) and Antitumor Benzothiazole Ligands as Potential Therapeutic Candidates

Antitumor benzothiazoles, including 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203; NSC 703786), non-fluorinated parent compound DF 203 (NSC 674495), and Phortress (NSC 710305), the lysyl amide prodrug of 5F 203, are experimental anticancer agents with activity in ovarian and breast cancer models in vitro and in vivo. These compounds require (and induce their own) metabolism by cytochrome P450 (CYP) enzymes (e.g., CYP1A1) for antitumor action. The aryl hydrocarbon receptor (AhR) is the main transcriptional regulator of CYP1A1, and we have previously demonstrated that DF 203 and 5F 203 are potent AhR ligands and trigger activation of AhR signaling in sensitive breast and ovarian cancer cells, causing nuclear translocation of AhR. We propose that AhR may represent a new molecular target in the treatment of ovarian tumors, and 5F 203 may exemplify a potential novel treatment. Furthermore, putative biomarkers of sensitivity to this agent have been identified

Cuprate addition to a 6-substituted pentafulvene: preparation of sec-alkyl substituted titanocene dichlorides and their biological activity

The copper-catalysed (10 mol-% CuBr·SMe2, CuCN·LiCl or CuI/PPh3) addition of RMgBr to the pentafulvene 1-(cyclopenta-2,4-dien-1-ylidenemethyl)-2-methoxybenzene allows the formation of cyclopentadienyl derivatives with α-CHR(2-MeOPh) sidechains (R = Me, Et, nBu, iBu, allyl, Ph) without H– transfer. The deprotonation of these sec-alkyl-substituted cyclopentadienyls followed by the addition of TiCl4 allows the isolation of TiCl2{η5-C5H4CHR(2-OMePh)} as rac/meso mixtures that show activity against human colon, breast and pancreatic cell lines (GI50 2.3–42.4 μM)

Autophagy modulation: a prudent approach in cancer treatment?

Autophagy is a tightly controlled process comprising lysosomal degradation and recycling of cellular proteins and organelles. In cancer, its paradoxical dual role of cytoprotection and cytotoxicity is context-dependent and controversial. Autophagy primarily acts as a mechanism of tumour suppression, by maintenance of genomic integrity and prevention of proliferation and inflammation. This, combined with immune-surveillance capabilities and autophagy’s implicated role in cell death, acts to prevent tumour initiation. However, established tumours exploit autophagy to survive cellular stresses in the hostile tumour microenvironment. This can lead to therapy resistance, one of the biggest challenges facing current anti-cancer approaches. Autophagy modulation is an exciting area of clinical development, attempting to harness this fundamental process as an anti-cancer strategy. Autophagy induction could potentially prevent tumour formation and enhance anti-cancer immune responses. In addition, drug-induced autophagy could be used to kill cancer cells, particularly those in which the apoptotic machinery is defective. Conversely, autophagy inhibition may help to sensitise resistant cancer cells to conventional chemotherapies and specifically target autophagy-addicted tumours. Currently, hydroxychloroquine is in phase I and II clinical trials in combination with several standard chemotherapies, whereas direct, deliberate autophagy induction remains to be tested clinically. More comprehensive understanding of the roles of autophagy throughout different stages of carcinogenesis has potential to guide development of novel therapeutic strategies to eradicate cancer cells

The importance of identified cause-of-death information being available for public health surveillance, actions and research

An amendment to the South African Births and Deaths Registration Act has compromised efforts to strengthen local mortality surveillance to provide statistics for small areas and enable data linkage to provide information for public health actions. Internationally it has been recognised that a careful balance needs to be kept between protecting individual patient confidentiality and enabling effective public health intelligence to guide patient care and service delivery and prevent harmful exposures. This article describes the public health benefits of a local mortality surveillance system in the Western Cape Province, South Africa (SA), as well as its potential for improving the quality of vital statistics data with integration into the national civil registration and vital statistics system. It also identifies other important uses for identifiable cause-of-death data in SA that have been compromised by this legislation

Cytotoxicity and apoptotic activities of alpha-, gamma- and delta-tocotrienol isomers on human cancer cells

Background: Tocotrienols, especially the gamma isomer was discovered to possess cytotoxic effects associated with the induction of apoptosis in numerous cancers. Individual tocotrienol isomers are believed to induce dissimilar apoptotic mechanisms in different cancer types. This study was aimed to compare the cytotoxic potency of alpha-, gamma- and delta-tocotrienols, and to explore their resultant apoptotic mechanisms in human lung adenocarcinoma A549 and glioblastoma U87MG cells which are scarcely researched. Methods: The cytotoxic effects of alpha-, gamma- and delta-tocotrienols in both A549 and U87MG cancer cells were first determined at the cell viability and morphological aspects. DNA damage types were then identified by comet assay and flow cytometric study was carried out to support the incidence of apoptosis. The involvements of caspase-8, Bid, Bax and mitochondrial membrane permeability (MMP) in the execution of apoptosis were further expounded. Results: All tocotrienols inhibited the growth of A549 and U87MG cancer cells in a concentration- and time-dependent manner. These treated cancer cells demonstrated some hallmarks of apoptotic morphologies, apoptosis was further confirmed by cell accumulation at the pre-G1 stage. All tocotrienols induced only double strand DNA breaks (DSBs) and no single strand DNA breaks (SSBs) in both treated cancer cells. Activation of caspase-8 leading to increased levels of Bid and Bax as well as cytochrome c release attributed by the disruption of mitochondrial membrane permeability in both A549 and U87MG cells were evident. Conclusions: This study has shown that delta-tocotrienol, in all experimental approaches, possessed a higher efficacy (shorter induction period) and effectiveness (higher induction rate) in the execution of apoptosis in both A549 and U87MG cancer cells as compared to alpha- and gamma-tocotrienols. Tocotrienols in particular the delta isomer can be an alternative chemotherapeutic agent for treating lung and brain cancers

Acalypha wilkesiana ethyl acetate extract enhances the in vitro cytotoxic effects of α-tocopherol in human brain and lung cancer cells

Multi-combinatorial approachesare considered nowadays to enhance the effectiveness of cancer treatment. In this study, α-tocopherol was tested in combination with the ethyl acetate extract from Acalypha wilkesiana for cytotoxicity activity against U87MG and A549 cell lines. The GI50 values for α-tocopherol against U87MG and A549 cells were 0.923±0.411μg/ml and 5.290±1.952μg/ml respectively in cell viability tests; when A. wilkesiana extract was added in adjunct with the treatment of α-tocopherol in minimum inhibitory concentration (MIC), the GI50 values of α-tocopherol improved significantly (p<0.05) to <0.43μg/ml (1μM) for both cell lines tested. Histological staining signified that both α-tocopherol and A. wilkesiana extract treated cancer cell lines exhibited apoptotic morphological characteristics. Single cell gel electrophoresis (SCGE) comet assays revealed that α-tocopherol caused only double strand DNA breaks; whereas A. wilkesiana extract caused both single strand and double strand DNA breaks in U87MG and A549 cells. It is proposed that α-tocopherol and A. wilkesiana extract might trigger apoptosis in both U87MG and A549 cells through different apoptotic pathways that might complement each other to enhance their antiproliferative efficacy against the cancer cells

The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun

© 2020 The Author(s). Background: Acute myeloid leukemia (AML) is a heterogenous hematological malignancy with poor long-term survival. New drugs which improve the outcome of AML patients are urgently required. In this work, the activity and mechanism of action of the cytotoxic indole alkaloid Jerantinine B (JB), was examined in AML cells. Methods: We used a combination of proliferation and apoptosis assays to assess the effect of JB on AML cell lines and patient samples, with BH3 profiling being performed to identify early effects of the drug (4 h). Phosphokinase arrays were adopted to identify potential driver proteins in the cellular response to JB, the results of which were confirmed and extended using western blotting and inhibitor assays and measuring levels of reactive oxygen species. Results: AML cell growth was significantly impaired following JB exposure in a dose-dependent manner; potent colony inhibition of primary patient cells was also observed. An apoptotic mode of death was demonstrated using Annexin V and upregulation of apoptotic biomarkers (active caspase 3 and cleaved PARP). Using BH3 profiling, JB was shown to prime cells to apoptosis at an early time point (4 h) and phospho-kinase arrays demonstrated this to be associated with a strong upregulation and activation of both total and phosphorylated c-Jun (S63). The mechanism of c-Jun activation was probed and significant induction of reactive oxygen species (ROS) was demonstrated which resulted in an increase in the DNA damage response marker γH2AX. This was further verified by the loss of JB-induced C-Jun activation and maintenance of cell viability when using the ROS scavenger N-acetyl-L-cysteine (NAC). Conclusions: This work provides the first evidence of cytotoxicity of JB against AML cells and identifies ROS-induced c-Jun activation as the major mechanism of action

New treatments in renal cancer: The AhR ligands

Kidney cancer rapidly acquires resistance to antiangiogenic agents, such as sunitinib, developing an aggressive migratory phenotype (facilitated by c-Metsignal transduction). The Aryl hydrocarbon receptor (AhR) has recently been postulated as a molecular target for cancer treatment. Currently, there are two antitumor agent AhR ligands, with activity against renal cancer, that have been tested clinically: aminoflavone (AFP 464, NSC710464) and the benzothiazole (5F 203) prodrug Phortress. Our studies investigated the action of AFP 464, the aminoflavone pro-drug currently used in clinical trials, and 5F 203 on renal cancer cells, specifically examining their effects on cell cycle progression, apoptosis and cell migration. Both compounds caused cell cycle arrest and apoptosis but only 5F 203 potently inhibited the migration of TK-10, Caki-1 and SN12C cells as well as the migration signal transduction cascade, involving c-Met signaling, in TK-10 cells. Current investigations are focused on the development of nano-delivery vehicles, apoferritin-encapsulated benzothiazoles 5F 203 and GW610, for the treatment of renal cancer. These compounds have shown improved antitumor effects against TK-10 cells in vitro at lower concentrations compared with a naked agent.Fil: Itkin, Boris. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Breen, Alastair. University of Nottingham; Estados UnidosFil: Turyanska, Lyudmila. University of Nottingham; Estados UnidosFil: Sandes, Eduardo Omar. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Bradshaw, Tracey D.. University of Nottingham; Estados UnidosFil: Loaiza Perez, Andrea Irene. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin