In vitro analysis of putative cancer stem cell populations and chemosensitivity in the SW480 and SW620 colon cancer metastasis model:
- Slater, Cindy, de la Mare, Jo-Anne, Edkins, Adrienne L
- Authors: Slater, Cindy , de la Mare, Jo-Anne , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164401 , vital:41115 , DOI: 10.3892/ol.2018.8431
- Description: The cancer stem cell (CSC) theory implicates a small subpopulation of cells with stem like properties, which is responsible for tumour initiation, development and metastasis. The unique biological and functional characteristics of CSCs, widely associated with treatment resistance, indicate an association between metastasis and stemness. It was hypothesised that metastatic cell lines may be enriched in CSCs and that this would correlate with a more resistant tumour. In the present study, the SW480 and SW620 paired cell lines derived from a colon adenocarcinoma and its lymph node metastasis, respectively were compared as an in vitro model of cancer progression. Their chemosensitivity and CSC properties were investigated. A range of in vitro assays were performed, including the side population assay, ALDEFLUOR assay, tumoursphere assay and assessment of CSC associated surface phenotypes.
- Full Text:
- Authors: Slater, Cindy , de la Mare, Jo-Anne , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164401 , vital:41115 , DOI: 10.3892/ol.2018.8431
- Description: The cancer stem cell (CSC) theory implicates a small subpopulation of cells with stem like properties, which is responsible for tumour initiation, development and metastasis. The unique biological and functional characteristics of CSCs, widely associated with treatment resistance, indicate an association between metastasis and stemness. It was hypothesised that metastatic cell lines may be enriched in CSCs and that this would correlate with a more resistant tumour. In the present study, the SW480 and SW620 paired cell lines derived from a colon adenocarcinoma and its lymph node metastasis, respectively were compared as an in vitro model of cancer progression. Their chemosensitivity and CSC properties were investigated. A range of in vitro assays were performed, including the side population assay, ALDEFLUOR assay, tumoursphere assay and assessment of CSC associated surface phenotypes.
- Full Text:
LRP1 is required for novobiocin-mediated fibronectin turnover:
- Boel, Natasha M-E, Hunter, Morgan C, Edkins, Adrienne L
- Authors: Boel, Natasha M-E , Hunter, Morgan C , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164896 , vital:41182 , DOI: 10.1038/s41598-018-29531-2
- Description: Fibronectin (FN) plays a major role in the stability and organization of the extracellular matrix (ECM). We have previously demonstrated that FN interacts directly with Hsp90, as well as showing that the Hsp90 inhibitor novobiocin results in FN turnover via a receptor mediated process. However, the receptor involved has not been previously identified. LRP1 is a ubiquitous receptor responsible for the internalisation of numerous ligands that binds both Hsp90 and FN, and therefore we investigated whether LRP1 was involved in novobiocin-mediated FN turnover.
- Full Text:
- Authors: Boel, Natasha M-E , Hunter, Morgan C , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164896 , vital:41182 , DOI: 10.1038/s41598-018-29531-2
- Description: Fibronectin (FN) plays a major role in the stability and organization of the extracellular matrix (ECM). We have previously demonstrated that FN interacts directly with Hsp90, as well as showing that the Hsp90 inhibitor novobiocin results in FN turnover via a receptor mediated process. However, the receptor involved has not been previously identified. LRP1 is a ubiquitous receptor responsible for the internalisation of numerous ligands that binds both Hsp90 and FN, and therefore we investigated whether LRP1 was involved in novobiocin-mediated FN turnover.
- Full Text:
NMR structural elucidation of channaine, an unusual alkaloid from Sceletium tortuosum:
- Veale, Clinton G L, Chen, Weiyang, Chaudhary, Sushil, Kituyi, Sarah N, Isaacs, Michelle, Hoppe, Heinrich C, Edkins, Adrienne L, Combrinck, Sandra, Mehari, Bewketu, Viljoen, Alvaro
- Authors: Veale, Clinton G L , Chen, Weiyang , Chaudhary, Sushil , Kituyi, Sarah N , Isaacs, Michelle , Hoppe, Heinrich C , Edkins, Adrienne L , Combrinck, Sandra , Mehari, Bewketu , Viljoen, Alvaro
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164345 , vital:41110 , DOI: 10.1016/j.phytol.2017.11.018
- Description: Chemical interrogation of the Sceletium genus and Amaryllidaceae family of plants has yielded a diverse array of aryl-hydroindole containing alkaloids. Included in this class is channaine, which was tentatively identified, without comprehensive structural elucidation from Sceletium tortuosum in 1957. Following its isolation from S. strictum, the structure of channaine was eventually resolved by X-ray crystallographic analysis, which revealed an unusual cage-like ring structure at the interface of two aryl-hydroindole subunits. However, since this report in 1978, channaine has not re-appeared in the literature. In this letter, the full NMR characterisation of channaine, isolated from S. tortuosum collected from St Helena in the Western Cape Province of South Africa, is reported for the first time.
- Full Text:
- Authors: Veale, Clinton G L , Chen, Weiyang , Chaudhary, Sushil , Kituyi, Sarah N , Isaacs, Michelle , Hoppe, Heinrich C , Edkins, Adrienne L , Combrinck, Sandra , Mehari, Bewketu , Viljoen, Alvaro
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164345 , vital:41110 , DOI: 10.1016/j.phytol.2017.11.018
- Description: Chemical interrogation of the Sceletium genus and Amaryllidaceae family of plants has yielded a diverse array of aryl-hydroindole containing alkaloids. Included in this class is channaine, which was tentatively identified, without comprehensive structural elucidation from Sceletium tortuosum in 1957. Following its isolation from S. strictum, the structure of channaine was eventually resolved by X-ray crystallographic analysis, which revealed an unusual cage-like ring structure at the interface of two aryl-hydroindole subunits. However, since this report in 1978, channaine has not re-appeared in the literature. In this letter, the full NMR characterisation of channaine, isolated from S. tortuosum collected from St Helena in the Western Cape Province of South Africa, is reported for the first time.
- Full Text:
Regulation of the extracellular matrix by heat shock proteins and molecular chaperones:
- Boel, Natasha M-E, Edkins, Adrienne L
- Authors: Boel, Natasha M-E , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/164368 , vital:41112 , ISBN 978-3-319-69040-7 , DOI: 10.1007/978-3-319-69042-1_6
- Description: The extracellular matrix (ECM) serves as a scaffold for cells within tissues and is composed of an intricate network of glycoproteins, growth factors and matricellular proteins which cooperatively function in cell processes such as migration, adhesion and wound healing. ECM morphology is constantly undergoing remodelling (synthesis, assembly and degradation) during normal cell processes and when deregulated may contribute to disease. Heat shock proteins (Hsps) are involved in regulating processes that determine the assembly and degradation of the ECM at multiple levels, in both normal and diseased states. These roles include mediating the activation of ECM-degrading enzymes, maintaining matrix stability and clearing aggregated/misfolded proteins. Hsp may serve as chaperones and receptors or have cytokine-like functions. In this chapter, we review how Hsp90, Hsp70, Hsp40 and a number of ER resident chaperones contribute to ECM regulation. The role of the non-Hsp chaperones, SPARC and clusterin in the ECM is also discussed.
- Full Text:
- Authors: Boel, Natasha M-E , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/164368 , vital:41112 , ISBN 978-3-319-69040-7 , DOI: 10.1007/978-3-319-69042-1_6
- Description: The extracellular matrix (ECM) serves as a scaffold for cells within tissues and is composed of an intricate network of glycoproteins, growth factors and matricellular proteins which cooperatively function in cell processes such as migration, adhesion and wound healing. ECM morphology is constantly undergoing remodelling (synthesis, assembly and degradation) during normal cell processes and when deregulated may contribute to disease. Heat shock proteins (Hsps) are involved in regulating processes that determine the assembly and degradation of the ECM at multiple levels, in both normal and diseased states. These roles include mediating the activation of ECM-degrading enzymes, maintaining matrix stability and clearing aggregated/misfolded proteins. Hsp may serve as chaperones and receptors or have cytokine-like functions. In this chapter, we review how Hsp90, Hsp70, Hsp40 and a number of ER resident chaperones contribute to ECM regulation. The role of the non-Hsp chaperones, SPARC and clusterin in the ECM is also discussed.
- Full Text:
Extracellular Hsp90 and TGFP regulate adhesion, migration and anchorage independent growth in a paired colon cancer cell line model
- de la Mare, Jo-Anne, Jurgens, Tamarin, Edkins, Adrienne L
- Authors: de la Mare, Jo-Anne , Jurgens, Tamarin , Edkins, Adrienne L
- Date: 2017
- Language: English
- Type: article , text
- Identifier: http://hdl.handle.net/10962/59920 , vital:27710 , https://doi.org/10.1186/s12885-017-3190-z
- Description: Tumour metastasis remains the major cause of death in cancer patients and, to date, the mechanism and signalling pathways governing this process are not completely understood. The TGF-ß pathway is the most commonly mutated pathway in cancer, however its role in cancer progression is controversial as it can function as both a promoter and a suppressor of metastasis. Although previous studies have suggested a role for the molecular chaperone Hsp90 in regulating the TGF-ß pathway, the level at which this occurs as well as the consequences in terms of colon cancer metastasis are unknown.
- Full Text:
- Authors: de la Mare, Jo-Anne , Jurgens, Tamarin , Edkins, Adrienne L
- Date: 2017
- Language: English
- Type: article , text
- Identifier: http://hdl.handle.net/10962/59920 , vital:27710 , https://doi.org/10.1186/s12885-017-3190-z
- Description: Tumour metastasis remains the major cause of death in cancer patients and, to date, the mechanism and signalling pathways governing this process are not completely understood. The TGF-ß pathway is the most commonly mutated pathway in cancer, however its role in cancer progression is controversial as it can function as both a promoter and a suppressor of metastasis. Although previous studies have suggested a role for the molecular chaperone Hsp90 in regulating the TGF-ß pathway, the level at which this occurs as well as the consequences in terms of colon cancer metastasis are unknown.
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Ferrocenyl and organic novobiocin derivatives: synthesis and their in vitro biological activity
- Mbaba, Mziyanda, Mabhula, Amanda N, Boel, Natasha, Edkins, Adrienne L, Isaacs, Michelle, Hoppe, Heinrich C, Khanye, Setshaba D
- Authors: Mbaba, Mziyanda , Mabhula, Amanda N , Boel, Natasha , Edkins, Adrienne L , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66189 , vital:28914 , https://doi.org/10.1016/j.jinorgbio.2017.04.014
- Description: publisher version , A focused series of novobiocin derivatives containing a ferrocene unit together with their corresponding organic novobiocin analogues have been synthesized in modest to good yields. These compounds were screened for biological activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) and human breast cancer cell line (HCC38). With the exception of compounds 5c and 5d, the general trend observed is that incorporation of the ferrocene moiety into novobiocin scaffold resulted in compounds 6a–d/6f showing enhanced activity compared to organic analogues 5a–b and 5e–f.
- Full Text: false
- Authors: Mbaba, Mziyanda , Mabhula, Amanda N , Boel, Natasha , Edkins, Adrienne L , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66189 , vital:28914 , https://doi.org/10.1016/j.jinorgbio.2017.04.014
- Description: publisher version , A focused series of novobiocin derivatives containing a ferrocene unit together with their corresponding organic novobiocin analogues have been synthesized in modest to good yields. These compounds were screened for biological activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) and human breast cancer cell line (HCC38). With the exception of compounds 5c and 5d, the general trend observed is that incorporation of the ferrocene moiety into novobiocin scaffold resulted in compounds 6a–d/6f showing enhanced activity compared to organic analogues 5a–b and 5e–f.
- Full Text: false
Fibronectin is a stress responsive gene regulated by HSF1 in response to geldanamycin
- Dhanani, Karim C H, Samson, William J, Edkins, Adrienne L
- Authors: Dhanani, Karim C H , Samson, William J , Edkins, Adrienne L
- Date: 2017
- Language: English
- Type: article , text
- Identifier: http://hdl.handle.net/10962/59931 , vital:27711 , https://doi:10.1038/s41598-017-18061-y
- Description: Fibronectin is an extracellular matrix glycoprotein with key roles in cell adhesion and migration. Hsp90 binds directly to fibronectin and Hsp90 depletion regulates fibronectin matrix stability. Where inhibition of Hsp90 with a C-terminal inhibitor, novobiocin, reduced the fibronectin matrix, treatment with an N-terminal inhibitor, geldanamycin, increased fibronectin levels. Geldanamycin treatment induced a stress response and a strong dose and time dependent increase in fibronectin mRNA via activation of the fibronectin promoter. Three putative heat shock elements (HSEs) were identified in the fibronectin promoter. Loss of two of these HSEs reduced both basal and geldanamycin-induced promoter activity, as did inhibition of the stress-responsive transcription factor HSF1. Binding of HSF1 to one of the putative HSE was confirmed by ChIP under basal conditions, and occupancy shown to increase with geldanamycin treatment. These data support the hypothesis that fibronectin is stress-responsive and a functional HSF1 target gene. COLA42 and LAMB3 mRNA levels were also increased with geldanamycin indicating that regulation of extracellular matrix (ECM) genes by HSF1 may be a wider phenomenon. Taken together, these data have implications for our understanding of ECM dynamics in stress-related diseases in which HSF1 is activated, and where the clinical application of N-terminal Hsp90 inhibitors is intended.
- Full Text:
- Authors: Dhanani, Karim C H , Samson, William J , Edkins, Adrienne L
- Date: 2017
- Language: English
- Type: article , text
- Identifier: http://hdl.handle.net/10962/59931 , vital:27711 , https://doi:10.1038/s41598-017-18061-y
- Description: Fibronectin is an extracellular matrix glycoprotein with key roles in cell adhesion and migration. Hsp90 binds directly to fibronectin and Hsp90 depletion regulates fibronectin matrix stability. Where inhibition of Hsp90 with a C-terminal inhibitor, novobiocin, reduced the fibronectin matrix, treatment with an N-terminal inhibitor, geldanamycin, increased fibronectin levels. Geldanamycin treatment induced a stress response and a strong dose and time dependent increase in fibronectin mRNA via activation of the fibronectin promoter. Three putative heat shock elements (HSEs) were identified in the fibronectin promoter. Loss of two of these HSEs reduced both basal and geldanamycin-induced promoter activity, as did inhibition of the stress-responsive transcription factor HSF1. Binding of HSF1 to one of the putative HSE was confirmed by ChIP under basal conditions, and occupancy shown to increase with geldanamycin treatment. These data support the hypothesis that fibronectin is stress-responsive and a functional HSF1 target gene. COLA42 and LAMB3 mRNA levels were also increased with geldanamycin indicating that regulation of extracellular matrix (ECM) genes by HSF1 may be a wider phenomenon. Taken together, these data have implications for our understanding of ECM dynamics in stress-related diseases in which HSF1 is activated, and where the clinical application of N-terminal Hsp90 inhibitors is intended.
- Full Text:
Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective
- Edkins, Adrienne L, Price, John T, Pockley, A Graham, Blatch, Gregory L
- Authors: Edkins, Adrienne L , Price, John T , Pockley, A Graham , Blatch, Gregory L
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164332 , vital:41109 , DOI: 10.1098/rstb.2016.0521
- Description: Many heat shock proteins (HSPs) are essential to survival as a consequence of their role as molecular chaperones, and play a critical role in maintaining cellular proteostasis by integrating the fundamental processes of protein folding and degradation. HSPs are arguably among the most prominent classes of proteins that have been broadly linked to many human disorders, with changes in their expression profile and/or intracellular/extracellular location now being described as contributing to the pathogenesis of a number of different diseases. Although the concept was initially controversial, it is now widely accepted that HSPs have additional biological functions over and above their role in proteostasis (so-called ‘protein moonlighting’).
- Full Text:
- Authors: Edkins, Adrienne L , Price, John T , Pockley, A Graham , Blatch, Gregory L
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164332 , vital:41109 , DOI: 10.1098/rstb.2016.0521
- Description: Many heat shock proteins (HSPs) are essential to survival as a consequence of their role as molecular chaperones, and play a critical role in maintaining cellular proteostasis by integrating the fundamental processes of protein folding and degradation. HSPs are arguably among the most prominent classes of proteins that have been broadly linked to many human disorders, with changes in their expression profile and/or intracellular/extracellular location now being described as contributing to the pathogenesis of a number of different diseases. Although the concept was initially controversial, it is now widely accepted that HSPs have additional biological functions over and above their role in proteostasis (so-called ‘protein moonlighting’).
- Full Text:
Isolation, characterization and antiproliferative activity of new metabolites from the South African endemic red algal species Laurencia alfredensis
- Dziwornu, Godwin A, Caira, Mino R, de la Mare, Jo-Anne, Edkins, Adrienne L, Bolton, John J, Beukes, Denzil R, Sunassee, Suthananda N
- Authors: Dziwornu, Godwin A , Caira, Mino R , de la Mare, Jo-Anne , Edkins, Adrienne L , Bolton, John J , Beukes, Denzil R , Sunassee, Suthananda N
- Date: 2017
- Language: English
- Type: article , text
- Identifier: http://hdl.handle.net/10962/59963 , vital:27715 , https://doi:10.3390/molecules22040513
- Description: The marine red algae of the genus Laurencia have been widely studied for their structurally diverse and biologically active secondary metabolites. We report here the natural product investigation of the organic extract of a newly identified South African endemic species, Laurencia alfredensis. A sequence of column chromatography, preparative TLC and normal phase HPLC resulted in the isolation of eleven compounds comprising three labdane-type diterpenes (1-3), four polyether triterpenes (4-7), three cholestane-type ecdysteroids (8-10) and a glycolipid (11). Compounds 1-3, 5-8 and 10 have not previously been reported, while compound 9 is reported here for the first time from a natural source and the known compound 11 isolated for the first time from the genus Laurencia. The structural elucidation and the relative configuration assignments of the compounds were accomplished by extensive use of ID- and 2D-NMR, HR-ESI-MS, UV and IR spectroscopic techniques, while the absolute configuration of compound 1 was determined by single-crystal X-ray diffraction analysis. All compounds were evaluated against the MDA-MB-231 breast and HeLa cervical cancer cell lines. Compound 2 exhibited low micromolar antiproliferative activity (IC50 = 9.3 gM) against the triple negative breast carcinoma and compound 7 was similarly active (IC50 = 8.8 gM) against the cervical cancer cell line.
- Full Text:
- Authors: Dziwornu, Godwin A , Caira, Mino R , de la Mare, Jo-Anne , Edkins, Adrienne L , Bolton, John J , Beukes, Denzil R , Sunassee, Suthananda N
- Date: 2017
- Language: English
- Type: article , text
- Identifier: http://hdl.handle.net/10962/59963 , vital:27715 , https://doi:10.3390/molecules22040513
- Description: The marine red algae of the genus Laurencia have been widely studied for their structurally diverse and biologically active secondary metabolites. We report here the natural product investigation of the organic extract of a newly identified South African endemic species, Laurencia alfredensis. A sequence of column chromatography, preparative TLC and normal phase HPLC resulted in the isolation of eleven compounds comprising three labdane-type diterpenes (1-3), four polyether triterpenes (4-7), three cholestane-type ecdysteroids (8-10) and a glycolipid (11). Compounds 1-3, 5-8 and 10 have not previously been reported, while compound 9 is reported here for the first time from a natural source and the known compound 11 isolated for the first time from the genus Laurencia. The structural elucidation and the relative configuration assignments of the compounds were accomplished by extensive use of ID- and 2D-NMR, HR-ESI-MS, UV and IR spectroscopic techniques, while the absolute configuration of compound 1 was determined by single-crystal X-ray diffraction analysis. All compounds were evaluated against the MDA-MB-231 breast and HeLa cervical cancer cell lines. Compound 2 exhibited low micromolar antiproliferative activity (IC50 = 9.3 gM) against the triple negative breast carcinoma and compound 7 was similarly active (IC50 = 8.8 gM) against the cervical cancer cell line.
- Full Text:
Cytotoxic activity of marine sponge extracts from the sub-Antarctic Islands and the Southern Ocean
- Olsen, Elisabeth, De Cerf, Christopher, Dziwornu, Godwin A, Puccinelli, Eleonora, Parker-Nance, Shirley, Ansorge, Isabelle J, Samaai, Toufiek, Dingle, Laura M K, Edkins, Adrienne L, Sunassee, Suthananda N
- Authors: Olsen, Elisabeth , De Cerf, Christopher , Dziwornu, Godwin A , Puccinelli, Eleonora , Parker-Nance, Shirley , Ansorge, Isabelle J , Samaai, Toufiek , Dingle, Laura M K , Edkins, Adrienne L , Sunassee, Suthananda N
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66300 , vital:28931 , https://doi.org/10.17159/sajs.2016/20160202
- Description: publisher version , Over the past 50 years, marine invertebrates, especially sponges, have proven to be a valuable source of new and/or bioactive natural products that have the potential to be further developed as lead compounds for pharmaceutical applications. Although marine benthic invertebrate communities occurring off the coast of South Africa have been explored for their biomedicinal potential, the natural product investigation of marine sponges from the sub-Antarctic Islands in the Southern Ocean for the presence of bioactive secondary metabolites has been relatively unexplored thus far. We report here the results for the biological screening of both aqueous and organic extracts prepared from nine specimens of eight species of marine sponges, collected from around Marion Island and the Prince Edward Islands in the Southern Ocean, for their cytotoxic activity against three cancer cell lines. The results obtained through this multidisciplinary collaborative research effort by exclusively South African institutions has provided an exciting opportunity to discover cytotoxic compounds from sub-Antarctic sponges, whilst contributing to our understanding of the biodiversity and geographic distributions of these cold-water invertebrates. Therefore, we acknowledge here the various contributions of the diverse scientific disciplines that played a pivotal role in providing the necessary platform for the future natural products chemistry investigation of these marine sponges from the sub- Antarctic Islands and the Southern Ocean. Significance: This study will contribute to understanding the biodiversity and geographic distributions of sponges in the Southern Ocean. This multidisciplinary project has enabled the investigation of marine sponges for the presence of cytotoxic compounds. Further investigation will lead to the isolation and identification of cytotoxic compounds present in the active sponge extracts. , University of Cape Town; South African Medical Research Council; National Research Foundation (South Africa); CANSA; Rhodes University; Department of Science and Technology; Department of Environmental Affairs; SANAP
- Full Text:
- Authors: Olsen, Elisabeth , De Cerf, Christopher , Dziwornu, Godwin A , Puccinelli, Eleonora , Parker-Nance, Shirley , Ansorge, Isabelle J , Samaai, Toufiek , Dingle, Laura M K , Edkins, Adrienne L , Sunassee, Suthananda N
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66300 , vital:28931 , https://doi.org/10.17159/sajs.2016/20160202
- Description: publisher version , Over the past 50 years, marine invertebrates, especially sponges, have proven to be a valuable source of new and/or bioactive natural products that have the potential to be further developed as lead compounds for pharmaceutical applications. Although marine benthic invertebrate communities occurring off the coast of South Africa have been explored for their biomedicinal potential, the natural product investigation of marine sponges from the sub-Antarctic Islands in the Southern Ocean for the presence of bioactive secondary metabolites has been relatively unexplored thus far. We report here the results for the biological screening of both aqueous and organic extracts prepared from nine specimens of eight species of marine sponges, collected from around Marion Island and the Prince Edward Islands in the Southern Ocean, for their cytotoxic activity against three cancer cell lines. The results obtained through this multidisciplinary collaborative research effort by exclusively South African institutions has provided an exciting opportunity to discover cytotoxic compounds from sub-Antarctic sponges, whilst contributing to our understanding of the biodiversity and geographic distributions of these cold-water invertebrates. Therefore, we acknowledge here the various contributions of the diverse scientific disciplines that played a pivotal role in providing the necessary platform for the future natural products chemistry investigation of these marine sponges from the sub- Antarctic Islands and the Southern Ocean. Significance: This study will contribute to understanding the biodiversity and geographic distributions of sponges in the Southern Ocean. This multidisciplinary project has enabled the investigation of marine sponges for the presence of cytotoxic compounds. Further investigation will lead to the isolation and identification of cytotoxic compounds present in the active sponge extracts. , University of Cape Town; South African Medical Research Council; National Research Foundation (South Africa); CANSA; Rhodes University; Department of Science and Technology; Department of Environmental Affairs; SANAP
- Full Text:
Heat shock protein inhibitors: success stories
- McAlpine, Shelli R, Edkins, Adrienne L
- Authors: McAlpine, Shelli R , Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/66359 , vital:28940 , https://doi.org/10.1007/978-3-319-32607-8
- Description: publisher version , Introduction: Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors. , This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98566), the Cancer Association of South Africa (CANSA), Medical Research Council South Africa (MRC-SA) and Rhodes University. The views expressed are those of the authors and should not be attributed to the DST, NRF, CANSA, MRC-SA or Rhodes University. We apologize if we have inadvertently missed any important contributions to the field.
- Full Text: false
- Authors: McAlpine, Shelli R , Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/66359 , vital:28940 , https://doi.org/10.1007/978-3-319-32607-8
- Description: publisher version , Introduction: Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors. , This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98566), the Cancer Association of South Africa (CANSA), Medical Research Council South Africa (MRC-SA) and Rhodes University. The views expressed are those of the authors and should not be attributed to the DST, NRF, CANSA, MRC-SA or Rhodes University. We apologize if we have inadvertently missed any important contributions to the field.
- Full Text: false
Hsp40 Co-chaperones as drug targets: towards the development of specific inhibitors
- Pesce, Eva-Rachele, Blatch, Gregory L, Edkins, Adrienne L
- Authors: Pesce, Eva-Rachele , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66335 , vital:28937 , https://doi.org/10.1007/7355_2015_92
- Description: publisher version , The heat shock protein 40 (Hsp40/DNAJ) family of co-chaperones modulates the activity of the major molecular chaperone heat shock protein 70 (Hsp70) protein group. Hsp40 stimulates the basal ATPase activity of Hsp70 and hence regulates the affinity of Hsp70 for substrate proteins. The number of Hsp40 genes in most organisms is substantially greater than the number of Hsp70 genes. Therefore, different Hsp40 family members may regulate different activities of the same Hsp70. This fact, along with increasing knowledge of the function of Hsp40 in diseases, has led to certain Hsp40 isoforms being considered promising drug targets. Here we review the role of Hsp40 in human disease and recent developments towards the creation of Hsp40-specific inhibitors.
- Full Text: false
- Authors: Pesce, Eva-Rachele , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66335 , vital:28937 , https://doi.org/10.1007/7355_2015_92
- Description: publisher version , The heat shock protein 40 (Hsp40/DNAJ) family of co-chaperones modulates the activity of the major molecular chaperone heat shock protein 70 (Hsp70) protein group. Hsp40 stimulates the basal ATPase activity of Hsp70 and hence regulates the affinity of Hsp70 for substrate proteins. The number of Hsp40 genes in most organisms is substantially greater than the number of Hsp70 genes. Therefore, different Hsp40 family members may regulate different activities of the same Hsp70. This fact, along with increasing knowledge of the function of Hsp40 in diseases, has led to certain Hsp40 isoforms being considered promising drug targets. Here we review the role of Hsp40 in human disease and recent developments towards the creation of Hsp40-specific inhibitors.
- Full Text: false
Hsp90 co-chaperones as drug targets in cancer: current perspectives
- Authors: Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66347 , vital:28938 , https://doi.org/10.1007/7355_2015_99
- Description: publisher version , Hsp90 is a molecular chaperone that regulates the function of numerous oncogenic transcription factors and signalling intermediates in the cell. Inhibition of Hsp90 is sufficient to induce the proteosomal degradation of many of these proteins, and as such, the Hsp90 chaperone has been regarded as a promising drug target. The appropriate functioning of the Hsp90 chaperone is dependent on its ATPase activity and interactions with a cohort of non-substrate accessory proteins known as co-chaperones. Co-chaperones associate with Hsp90 at all stages of the chaperone cycle and regulate a range of Hsp90 functions, including ATP hydrolysis and client protein binding and release. Given the ability of co-chaperones to organise the function of the Hsp90 molecular machine, these proteins are now regarded as potential drug targets. Herein the role of selected Hsp90 co-chaperones Hop, Cdc37, p23 and Aha1 as possible drug targets is discussed with a focus on cancer. , This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98566), the Cancer Association of South Africa (CANSA), Medical Research Council South Africa (MRC-SA) and Rhodes University. The views expressed are those of the authors and should not be attributed to the DST, NRF, CANSA, MRC-SA or Rhodes University. We apologize if we have inadvertently missed any important contributions to the field.
- Full Text: false
- Authors: Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66347 , vital:28938 , https://doi.org/10.1007/7355_2015_99
- Description: publisher version , Hsp90 is a molecular chaperone that regulates the function of numerous oncogenic transcription factors and signalling intermediates in the cell. Inhibition of Hsp90 is sufficient to induce the proteosomal degradation of many of these proteins, and as such, the Hsp90 chaperone has been regarded as a promising drug target. The appropriate functioning of the Hsp90 chaperone is dependent on its ATPase activity and interactions with a cohort of non-substrate accessory proteins known as co-chaperones. Co-chaperones associate with Hsp90 at all stages of the chaperone cycle and regulate a range of Hsp90 functions, including ATP hydrolysis and client protein binding and release. Given the ability of co-chaperones to organise the function of the Hsp90 molecular machine, these proteins are now regarded as potential drug targets. Herein the role of selected Hsp90 co-chaperones Hop, Cdc37, p23 and Aha1 as possible drug targets is discussed with a focus on cancer. , This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98566), the Cancer Association of South Africa (CANSA), Medical Research Council South Africa (MRC-SA) and Rhodes University. The views expressed are those of the authors and should not be attributed to the DST, NRF, CANSA, MRC-SA or Rhodes University. We apologize if we have inadvertently missed any important contributions to the field.
- Full Text: false
Sarqaquinoic acid and related synthetic naphthoquinones inhibit the function of Hsp90
- Chiwakata, M, de la Mare, Jo-Anne, Edkins, Adrienne L, Beukes, Denzil R
- Authors: Chiwakata, M , de la Mare, Jo-Anne , Edkins, Adrienne L , Beukes, Denzil R
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66324 , vital:28933 , https://doi.org/10.1055/s-0036-1596751
- Description: publisher version , Heat shock protein 90 (Hsp90) is of critical importance in the proper folding of numerous proteins, including those involved in cancer. Consequently, there is significant interest in the discovery and development of Hsp90 inhibitors as anticancer drugs. In this study, we investigated the ability of sargaquinoic acid (SQA) and selected naphthoquinone derivatives to inhibit Hsp90 function. SQA was isolated and purified from Sargassum incisifolium while the naphthoquinones were synthesised via a straightforward sequence incorporating a Diels-Alder reaction between benzoquinone derivatives and myrcene followed by coupling with substituted alkyl or arylamines. Hsp90 inhibition was assessed by a client protein degradation assay. At a concentration of 1µM, SQA showed almost complete inhibition of Hsp90 but only moderate antiproliferative effects (IC50 658µM) against a Hs578T breast cancer carcinoma cell line. Interestingly, the most potent synthetic aminonaphthoquinone inhibited Hsp90 function by 50% at a concentration of 1µM but showed much improved activity against the Hs578T cell line (IC50 0.32µM). Furthermore, unlike geldanamycin, none of the compounds tested upregulates Hsp70 suggesting that these compounds may bind to the C-terminal end of Hsp90.
- Full Text: false
- Authors: Chiwakata, M , de la Mare, Jo-Anne , Edkins, Adrienne L , Beukes, Denzil R
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66324 , vital:28933 , https://doi.org/10.1055/s-0036-1596751
- Description: publisher version , Heat shock protein 90 (Hsp90) is of critical importance in the proper folding of numerous proteins, including those involved in cancer. Consequently, there is significant interest in the discovery and development of Hsp90 inhibitors as anticancer drugs. In this study, we investigated the ability of sargaquinoic acid (SQA) and selected naphthoquinone derivatives to inhibit Hsp90 function. SQA was isolated and purified from Sargassum incisifolium while the naphthoquinones were synthesised via a straightforward sequence incorporating a Diels-Alder reaction between benzoquinone derivatives and myrcene followed by coupling with substituted alkyl or arylamines. Hsp90 inhibition was assessed by a client protein degradation assay. At a concentration of 1µM, SQA showed almost complete inhibition of Hsp90 but only moderate antiproliferative effects (IC50 658µM) against a Hs578T breast cancer carcinoma cell line. Interestingly, the most potent synthetic aminonaphthoquinone inhibited Hsp90 function by 50% at a concentration of 1µM but showed much improved activity against the Hs578T cell line (IC50 0.32µM). Furthermore, unlike geldanamycin, none of the compounds tested upregulates Hsp70 suggesting that these compounds may bind to the C-terminal end of Hsp90.
- Full Text: false
Synthesis and evaluation of substituted 4-(N-benzylamino)cinnamate esters as potential anti-cancer agents and HIV-1 integrase inhibitors
- Faridoon, H, Edkins, Adrienne L, Isaacs, Michelle, Mnkandhla, Dumisani, Hoppe, Heinrich C, Kaye, Perry T
- Authors: Faridoon, H , Edkins, Adrienne L , Isaacs, Michelle , Mnkandhla, Dumisani , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66289 , vital:28929 , https://doi.org/10.1016/j.bmcl.2016.05.023
- Description: publisher version , Encouraging selectivity and low micromolar activity against HeLa cervical carcinoma (IC50 ⩾ 3.0 μM) and the aggressive MDA-MB-231 triple negative breast carcinoma (IC50 ⩾ 9.6 μM) cell lines has been exhibited by a number of readily accessible 4-(N-benzylamino)cinnamate esters. The potential of the ligands as HIV-1 integrase inhibitors has also been examined.
- Full Text: false
- Authors: Faridoon, H , Edkins, Adrienne L , Isaacs, Michelle , Mnkandhla, Dumisani , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66289 , vital:28929 , https://doi.org/10.1016/j.bmcl.2016.05.023
- Description: publisher version , Encouraging selectivity and low micromolar activity against HeLa cervical carcinoma (IC50 ⩾ 3.0 μM) and the aggressive MDA-MB-231 triple negative breast carcinoma (IC50 ⩾ 9.6 μM) cell lines has been exhibited by a number of readily accessible 4-(N-benzylamino)cinnamate esters. The potential of the ligands as HIV-1 integrase inhibitors has also been examined.
- Full Text: false
CHIP: a co-chaperone for degradation by the proteasome
- Authors: Edkins, Adrienne L
- Date: 2015
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/164863 , vital:41179 , ISBN 978-3-319-11730-0 , DOI: 10.1007/978-3-319-11731-7_11
- Description: Protein homeostasis relies on a balance between protein folding and protein degradation. Molecular chaperones like Hsp70 and Hsp90 fulfil well-defined roles in protein folding and conformational stability via ATP dependent reaction cycles. These folding cycles are controlled by associations with a cohort of non-client protein co-chaperones, such as Hop, p23 and Aha1. Pro-folding co-chaperones facilitate the transit of the client protein through the chaperone mediated folding process. However, chaperones are also involved in ubiquitin-mediated proteasomal degradation of client proteins. Similar to folding complexes, the ability of chaperones to mediate protein degradation is regulated by co-chaperones, such as the C terminal Hsp70 binding protein (CHIP).
- Full Text:
- Authors: Edkins, Adrienne L
- Date: 2015
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/164863 , vital:41179 , ISBN 978-3-319-11730-0 , DOI: 10.1007/978-3-319-11731-7_11
- Description: Protein homeostasis relies on a balance between protein folding and protein degradation. Molecular chaperones like Hsp70 and Hsp90 fulfil well-defined roles in protein folding and conformational stability via ATP dependent reaction cycles. These folding cycles are controlled by associations with a cohort of non-client protein co-chaperones, such as Hop, p23 and Aha1. Pro-folding co-chaperones facilitate the transit of the client protein through the chaperone mediated folding process. However, chaperones are also involved in ubiquitin-mediated proteasomal degradation of client proteins. Similar to folding complexes, the ability of chaperones to mediate protein degradation is regulated by co-chaperones, such as the C terminal Hsp70 binding protein (CHIP).
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Dynamic mitochondrial localisation of STAT3 in the cellular adipogenesis model 3T3-L1:
- Kramer, Adam H, Edkins, Adrienne L, Hoppe, Heinrich C, Prinsloo, Earl
- Authors: Kramer, Adam H , Edkins, Adrienne L , Hoppe, Heinrich C , Prinsloo, Earl
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164885 , vital:41181 , DOI: 10.1002/jcb.25076
- Description: A mechanistic relationship exists between protein localisation, activity and cellular differentiation. Understanding the contribution of these molecular mechanisms is required for elucidation of conditions that drive development. Literature suggests non‐canonical translocation of the Signal Transducer and Activator of Transcription 3 (STAT3) to the mitochondria contributes to the regulation of the electron transport chain, cellular respiration and reactive oxygen species production. Based on this we investigated the role of mitochondrial STAT3, specifically the serine 727 phosphorylated form, in cellular differentiation using the well‐defined mouse adipogenic model 3T3-L1.
- Full Text:
- Authors: Kramer, Adam H , Edkins, Adrienne L , Hoppe, Heinrich C , Prinsloo, Earl
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164885 , vital:41181 , DOI: 10.1002/jcb.25076
- Description: A mechanistic relationship exists between protein localisation, activity and cellular differentiation. Understanding the contribution of these molecular mechanisms is required for elucidation of conditions that drive development. Literature suggests non‐canonical translocation of the Signal Transducer and Activator of Transcription 3 (STAT3) to the mitochondria contributes to the regulation of the electron transport chain, cellular respiration and reactive oxygen species production. Based on this we investigated the role of mitochondrial STAT3, specifically the serine 727 phosphorylated form, in cellular differentiation using the well‐defined mouse adipogenic model 3T3-L1.
- Full Text:
Facile synthesis and biological evaluation of assorted indolyl-3-amides and esters from a single, stable carbonyl nitrile intermediate
- Veale, Clinton G L, Edkins, Adrienne L, de la Mare, Jo-Anne, de Kock, Carmen, Smith, Peter J, Khanye, Setshaba D
- Authors: Veale, Clinton G L , Edkins, Adrienne L , de la Mare, Jo-Anne , de Kock, Carmen , Smith, Peter J , Khanye, Setshaba D
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66221 , vital:28919 , https://doi.org/10.1016/j.tetlet.2015.02.090
- Description: publisher version , The synthesis of biologically relevant amides and esters is routinely conducted under complex reaction conditions or requires the use of additional catalysts in order to generate sensitive electrophilic species for attack by a nucleophile. Here we present the synthesis of different indolic esters and amides from indolyl-3-carbonyl nitrile, without the requirement of anhydrous reaction conditions or catalysts. Additionally, we screened these compounds for potential in vitro antimalarial and anticancer activity, revealing 1H-indolyl-3-carboxylic acid 3-(indolyl-3-carboxamide)aminobenzyl ester to have moderate activity against both lines.
- Full Text: false
- Authors: Veale, Clinton G L , Edkins, Adrienne L , de la Mare, Jo-Anne , de Kock, Carmen , Smith, Peter J , Khanye, Setshaba D
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66221 , vital:28919 , https://doi.org/10.1016/j.tetlet.2015.02.090
- Description: publisher version , The synthesis of biologically relevant amides and esters is routinely conducted under complex reaction conditions or requires the use of additional catalysts in order to generate sensitive electrophilic species for attack by a nucleophile. Here we present the synthesis of different indolic esters and amides from indolyl-3-carbonyl nitrile, without the requirement of anhydrous reaction conditions or catalysts. Additionally, we screened these compounds for potential in vitro antimalarial and anticancer activity, revealing 1H-indolyl-3-carboxylic acid 3-(indolyl-3-carboxamide)aminobenzyl ester to have moderate activity against both lines.
- Full Text: false
Hsp70/Hsp90 organising protein (hop): beyond interactions with chaperones and prion proteins
- Baindur-Hudson, Swati, Edkins, Adrienne L, Blatch, Gregory L
- Authors: Baindur-Hudson, Swati , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2015
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/164852 , vital:41178 , ISBN 978-3-319-11730-0 , DOI: 10.1007/978-3-319-11731-7_3
- Description: The Hsp70/Hsp90 organising protein (Hop), also known as stress-inducible protein 1 (STI1), has received considerable attention for diverse cellular functions in both healthy and diseased states. There is extensive evidence that intracellular Hop is a co-chaperone of the major chaperones Hsp70 and Hsp90, playing an important role in the productive folding of Hsp90 client proteins. Consequently, Hop is implicated in a number of key signalling pathways, including aberrant pathways leading to cancer. However, Hop is also secreted and it is now well established that Hop also serves as a receptor for the prion protein, PrPC.
- Full Text:
- Authors: Baindur-Hudson, Swati , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2015
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/164852 , vital:41178 , ISBN 978-3-319-11730-0 , DOI: 10.1007/978-3-319-11731-7_3
- Description: The Hsp70/Hsp90 organising protein (Hop), also known as stress-inducible protein 1 (STI1), has received considerable attention for diverse cellular functions in both healthy and diseased states. There is extensive evidence that intracellular Hop is a co-chaperone of the major chaperones Hsp70 and Hsp90, playing an important role in the productive folding of Hsp90 client proteins. Consequently, Hop is implicated in a number of key signalling pathways, including aberrant pathways leading to cancer. However, Hop is also secreted and it is now well established that Hop also serves as a receptor for the prion protein, PrPC.
- Full Text:
The palladacycle, AJ-5, exhibits anti-tumour and anti-cancer stem cell activity in breast cancer cells:
- Aliwaini, Saeb, Peres, Jade, Kröger, Wendy L, Blanckenberg, Angelique, de la Mare, Jo-Anne, Edkins, Adrienne L, Mapolie, Selwyn, Prince, Sharon
- Authors: Aliwaini, Saeb , Peres, Jade , Kröger, Wendy L , Blanckenberg, Angelique , de la Mare, Jo-Anne , Edkins, Adrienne L , Mapolie, Selwyn , Prince, Sharon
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164874 , vital:41180 , DOI: 10.1016/j.canlet.2014.11.027
- Description: Breast cancer is the most common malignancy amongst women worldwide but despite enormous efforts to address this problem, there is still limited success with most of the current therapeutic strategies. The current study describes the anti-cancer activity of a binuclear palladacycle complex (AJ-5) in oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB-231) breast cancer cells as well as human breast cancer stem cells. AJ-5 is shown to induce DNA double strand breaks leading to intrinsic and extrinsic apoptosis and autophagy cell death pathways which are mediated by the p38 MAP kinase. This study provides evidence that AJ-5 is potentially an effective compound in the treatment of breast cancer.
- Full Text:
- Authors: Aliwaini, Saeb , Peres, Jade , Kröger, Wendy L , Blanckenberg, Angelique , de la Mare, Jo-Anne , Edkins, Adrienne L , Mapolie, Selwyn , Prince, Sharon
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164874 , vital:41180 , DOI: 10.1016/j.canlet.2014.11.027
- Description: Breast cancer is the most common malignancy amongst women worldwide but despite enormous efforts to address this problem, there is still limited success with most of the current therapeutic strategies. The current study describes the anti-cancer activity of a binuclear palladacycle complex (AJ-5) in oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB-231) breast cancer cells as well as human breast cancer stem cells. AJ-5 is shown to induce DNA double strand breaks leading to intrinsic and extrinsic apoptosis and autophagy cell death pathways which are mediated by the p38 MAP kinase. This study provides evidence that AJ-5 is potentially an effective compound in the treatment of breast cancer.
- Full Text: