A combination of platinum anticancer drugs and mangiferin causes increased efficacy in cancer cell lines
- Authors: Du Plessis-Stoman, Debbie
- Date: 2010
- Subjects: Cancer -- Chemotherapy , Antineoplastic agents , Platinum compounds -- Therapeutic use , Cancer cells
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10338 , http://hdl.handle.net/10948/d1016160
- Description: This thesis mainly deals with some biochemical aspects regarding the efficacy of novel platinum anticancer compounds alone and in combination with mangiferin, as part of a broader study in which both chemistry and biochemistry are involved. Various novel diamine and N-S donor chelate compounds of platinum II and IV have been developed in which factors such as stereochemistry, ligand exchange rate and biocompatibility were considered as additional parameters. In the first order testing, each of these compounds was tested with reference to their “killing” potential by comparing their rate of killing, over a period of 48 hours with those of cisplatin and oxaliplatin. Numerous novel compounds were tested in this way, using the MTT cell viability assay and the three cancer cell lines MCF7, HT29 and HeLa. Although only a few could be regarded as equal to or even better than cisplatin, CPA7 and oxaliplatin, the testing of these compounds on cancer cells provided useful knowledge for the further development of novel compounds. Three of the better compounds, namely Yol 25, Yol 29.1 and Mar 4.1.4 were selected for further studies, together with oxaliplatin and CPA7 as positive controls, to obtain more detailed knowledge of their anticancer action, both alone and when applied in combination with mangiferin. In addition to the above, resistant cells were produced for each of the three different cell lines tested and all the selected compounds, both in the presence and absence of mangiferin. The effects of these treatments on the activation of NFĸB when applied to normal and resistant cell lines were also investigated. All the compounds induced apoptosis in the cell lines tested as well as alter the DNA cycle at one or more phase. Additionally, combination of these compounds with mangiferin enhanced the above-mentioned effects. Mangiferin decreases the IC50 values of the platinum drugs by up to 3.4 times and, although mangiferin alone did not induce cell cycle arrest, the presence of mangiferin in combination with oxaliplatin and Yol 25 shows an earlier and greatly enhanced delay in the S-phase, while cells treated with CPA7, Yol 29.1 and Mar 4.1.4 in combination with mangiferin showed a later, but greatly enhanced delay in the S-phase. It was also found that mangiferin acts as an NFĸB inhibitor when applied in combination with these drugs, which, in turn, reduces the occurrence of resistance in the cell lines. Resistance to oxaliplatin was counteracted by the combination with mangiferin in HeLa and HT29, but not in MCF7 cells, while resistance to CPA7 was only counteracted in the MCF7 cell line. Yol 25 and Mar 4.1.4 did not seem to induce resistance in HeLa and MCF7 cells, but did in HT29 cells, whereas Yol 29.1 caused resistance in HeLa and HT29 cells, but not in MCF7 cells. Finally, an effort was made to evaluate the different compounds by comparing them with respect to their properties relating to anticancer action with and without the addition of mangiferin.
- Full Text:
- Date Issued: 2010
- Authors: Du Plessis-Stoman, Debbie
- Date: 2010
- Subjects: Cancer -- Chemotherapy , Antineoplastic agents , Platinum compounds -- Therapeutic use , Cancer cells
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10338 , http://hdl.handle.net/10948/d1016160
- Description: This thesis mainly deals with some biochemical aspects regarding the efficacy of novel platinum anticancer compounds alone and in combination with mangiferin, as part of a broader study in which both chemistry and biochemistry are involved. Various novel diamine and N-S donor chelate compounds of platinum II and IV have been developed in which factors such as stereochemistry, ligand exchange rate and biocompatibility were considered as additional parameters. In the first order testing, each of these compounds was tested with reference to their “killing” potential by comparing their rate of killing, over a period of 48 hours with those of cisplatin and oxaliplatin. Numerous novel compounds were tested in this way, using the MTT cell viability assay and the three cancer cell lines MCF7, HT29 and HeLa. Although only a few could be regarded as equal to or even better than cisplatin, CPA7 and oxaliplatin, the testing of these compounds on cancer cells provided useful knowledge for the further development of novel compounds. Three of the better compounds, namely Yol 25, Yol 29.1 and Mar 4.1.4 were selected for further studies, together with oxaliplatin and CPA7 as positive controls, to obtain more detailed knowledge of their anticancer action, both alone and when applied in combination with mangiferin. In addition to the above, resistant cells were produced for each of the three different cell lines tested and all the selected compounds, both in the presence and absence of mangiferin. The effects of these treatments on the activation of NFĸB when applied to normal and resistant cell lines were also investigated. All the compounds induced apoptosis in the cell lines tested as well as alter the DNA cycle at one or more phase. Additionally, combination of these compounds with mangiferin enhanced the above-mentioned effects. Mangiferin decreases the IC50 values of the platinum drugs by up to 3.4 times and, although mangiferin alone did not induce cell cycle arrest, the presence of mangiferin in combination with oxaliplatin and Yol 25 shows an earlier and greatly enhanced delay in the S-phase, while cells treated with CPA7, Yol 29.1 and Mar 4.1.4 in combination with mangiferin showed a later, but greatly enhanced delay in the S-phase. It was also found that mangiferin acts as an NFĸB inhibitor when applied in combination with these drugs, which, in turn, reduces the occurrence of resistance in the cell lines. Resistance to oxaliplatin was counteracted by the combination with mangiferin in HeLa and HT29, but not in MCF7 cells, while resistance to CPA7 was only counteracted in the MCF7 cell line. Yol 25 and Mar 4.1.4 did not seem to induce resistance in HeLa and MCF7 cells, but did in HT29 cells, whereas Yol 29.1 caused resistance in HeLa and HT29 cells, but not in MCF7 cells. Finally, an effort was made to evaluate the different compounds by comparing them with respect to their properties relating to anticancer action with and without the addition of mangiferin.
- Full Text:
- Date Issued: 2010
New platinum coordination compounds : their synthesis, characterization and anticancer application
- Authors: Oosthuizen, Lukas Marthinus
- Date: 2009
- Subjects: Platinum compounds , Antineoplastic agents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10430 , http://hdl.handle.net/10948/d1018795
- Description: The aim of this thesis was to investigate the properties of novel platinum compounds with possible potential as anticancer agents, and to determine how their behaviour could lead to a better understanding of the chemistry involved. The final criteria were improvement of their anticancer behaviour. Since many questions are still unanswered as to the role of sulfur in anticancer action, studies were undertaken to synthesize novel platinum(II) complexes having non-leaving groups consisting of a combination of an aromatic nitrogen and thioetherial sulfur capable of forming a five membered ring upon coordination. The structural unit was 1-methyl-2-methylthioalkyl/aryl. Numerous complexes formed by these ligands each having chloro, bromo, iodo and oxalato leaving groups were then fully characterized. The results obtained by the various synthetic methods were compared and explained in terms of the chemistry involved. The role of the sulfur donor was indicated in both the halo- and oxalato-complexes and proved to be strongly influenced by the nature of the leaving groups. Their differences are reflected in their anticancer behaviour. The study was extended to mononitroplatinum(IV) complexes, in view of the kinetically stable platinum(IV) compounds and advantages related to this. A specific mononitroplatinum(IV) complex which proved to have good anticancer and STAT 3 properties could according to the literature not be synthesized successfully in a good yield and a high degree of purity. The results of extensive studies showed that the main problem centred around the simultaneous reactions in equilibrium during the synthesis. A number of these species formed as a result of side reactions could be identified and their close separation factors indicated chromatographically. The mechanism of these reactions and the unstable intermediate species involved could be rationalized and compared to analogues in the literature. All the complexes studied were characterized by spectral and thermal methods both in solution as well as the solid state. Their anticancer behaviour towards three anticancer cell lines (Hela, MCF 7, Ht 29) were determined and acted as a guide towards possible structural modifications for their improved capability. Three crystal structures of platinum(II) complexes were determined. The extent of the ionization of the platinum(II) complexes as well the redox potentials (Pt(II) / Pt(IV)) of the platinum(IV) complexes were particularly important factors pertaining to their anticancer action.
- Full Text:
- Date Issued: 2009
- Authors: Oosthuizen, Lukas Marthinus
- Date: 2009
- Subjects: Platinum compounds , Antineoplastic agents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10430 , http://hdl.handle.net/10948/d1018795
- Description: The aim of this thesis was to investigate the properties of novel platinum compounds with possible potential as anticancer agents, and to determine how their behaviour could lead to a better understanding of the chemistry involved. The final criteria were improvement of their anticancer behaviour. Since many questions are still unanswered as to the role of sulfur in anticancer action, studies were undertaken to synthesize novel platinum(II) complexes having non-leaving groups consisting of a combination of an aromatic nitrogen and thioetherial sulfur capable of forming a five membered ring upon coordination. The structural unit was 1-methyl-2-methylthioalkyl/aryl. Numerous complexes formed by these ligands each having chloro, bromo, iodo and oxalato leaving groups were then fully characterized. The results obtained by the various synthetic methods were compared and explained in terms of the chemistry involved. The role of the sulfur donor was indicated in both the halo- and oxalato-complexes and proved to be strongly influenced by the nature of the leaving groups. Their differences are reflected in their anticancer behaviour. The study was extended to mononitroplatinum(IV) complexes, in view of the kinetically stable platinum(IV) compounds and advantages related to this. A specific mononitroplatinum(IV) complex which proved to have good anticancer and STAT 3 properties could according to the literature not be synthesized successfully in a good yield and a high degree of purity. The results of extensive studies showed that the main problem centred around the simultaneous reactions in equilibrium during the synthesis. A number of these species formed as a result of side reactions could be identified and their close separation factors indicated chromatographically. The mechanism of these reactions and the unstable intermediate species involved could be rationalized and compared to analogues in the literature. All the complexes studied were characterized by spectral and thermal methods both in solution as well as the solid state. Their anticancer behaviour towards three anticancer cell lines (Hela, MCF 7, Ht 29) were determined and acted as a guide towards possible structural modifications for their improved capability. Three crystal structures of platinum(II) complexes were determined. The extent of the ionization of the platinum(II) complexes as well the redox potentials (Pt(II) / Pt(IV)) of the platinum(IV) complexes were particularly important factors pertaining to their anticancer action.
- Full Text:
- Date Issued: 2009
Novel aspects of platinum-amine coordination compounds: their chemistry and anticancer application
- Authors: Bouwer, Yolanda
- Date: 2008
- Subjects: Coordination compounds , Platinum compounds , Antineoplastic agents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10444 , http://hdl.handle.net/10948/d1021052
- Description: The aim in this thesis, was to synthesize novel platinum coordination compounds, in order to develop compounds with improved anticancer action which could lead to an improved understanding of the mechanism by which they operate and at the same time, improve synthetic methods for their products. The initial work included the development of a novel synthetic method for 1R,2R-diaminocyclohexaneoxalato-platinum(II) (oxaliplatin), by using an essentially non-aqueous solvent medium and direct ligand exchange at elevated temperatures. This was done by a study of the kinetics of the reaction in a variety of conditions; such as relative reagent concentrations and ratios as well as solvent mixtures. An effective method was developed which could be applied industrially. An international patent was taken out on this method. Various amine complexes of platinum(II) were synthesized using chloro, bromo and oxalato groups as leaving groups. The non-leaving groups were selected having certain specific characteristics in mind. Novel mononitroplatinum(IV) complexes were synthesized, mostly with oxalato leaving groups. One of these in particular, had excellent anticancer behaviour. Another trichloromononitro complex was also synthesized with very good anticancer properties. Two international patents were filed for the latter two compounds. As far as possible, all compounds were studied by spectrometric, chromatographic and thermal methods. They were also tested against 3 cancer cell lines namely cervical (Hela), Colon (HT29) and Breast (MCF7) cancer cells.
- Full Text:
- Date Issued: 2008
- Authors: Bouwer, Yolanda
- Date: 2008
- Subjects: Coordination compounds , Platinum compounds , Antineoplastic agents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10444 , http://hdl.handle.net/10948/d1021052
- Description: The aim in this thesis, was to synthesize novel platinum coordination compounds, in order to develop compounds with improved anticancer action which could lead to an improved understanding of the mechanism by which they operate and at the same time, improve synthetic methods for their products. The initial work included the development of a novel synthetic method for 1R,2R-diaminocyclohexaneoxalato-platinum(II) (oxaliplatin), by using an essentially non-aqueous solvent medium and direct ligand exchange at elevated temperatures. This was done by a study of the kinetics of the reaction in a variety of conditions; such as relative reagent concentrations and ratios as well as solvent mixtures. An effective method was developed which could be applied industrially. An international patent was taken out on this method. Various amine complexes of platinum(II) were synthesized using chloro, bromo and oxalato groups as leaving groups. The non-leaving groups were selected having certain specific characteristics in mind. Novel mononitroplatinum(IV) complexes were synthesized, mostly with oxalato leaving groups. One of these in particular, had excellent anticancer behaviour. Another trichloromononitro complex was also synthesized with very good anticancer properties. Two international patents were filed for the latter two compounds. As far as possible, all compounds were studied by spectrometric, chromatographic and thermal methods. They were also tested against 3 cancer cell lines namely cervical (Hela), Colon (HT29) and Breast (MCF7) cancer cells.
- Full Text:
- Date Issued: 2008
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