- Title
- An in vitro evaluation of anti-breast cancer activity of novel, heterocyclic aromatic compounds in combination with curcumin
- Creator
- Pereira, Melanie Claire
- Subject
- Breast -- Cancer Heterocyclic compounds
- Date Issued
- 2017
- Date
- 2017
- Type
- Thesis
- Type
- Doctoral
- Type
- PhD
- Identifier
- http://hdl.handle.net/10948/20416
- Identifier
- vital:29284
- Description
- Nearly two thirds of breast cancers are classified as estrogen receptor positive. Estrogen receptor (+) breast cancer is usually treated with anti-estrogen therapy, using Tamoxifen as the primary standard of treatment. Unfortunately, resistance to Tamoxifen is known to occur after 1 to 3 years of Tamoxifen therapy. For this reason, improved treatment strategies for ER (+) breast cancer are urgently needed. The general toxicity exerted by most anti-cancer drugs on proliferating cells, as well as some normal cells, restricts their therapeutic use. Novel cytotoxic agents developed with unique mechanisms of action have not been therapeutically suitable, since many of these compounds lack tumour selectivity. The adverse effects and the inefficacies of most chemotherapeutic therapies have motivated extensive investigations of alternatives. Numerous studies have demonstrated the advantages of using combination therapy with naturally-derived agents as an alternative, due to the higher therapeutic efficacy; with the added benefit of lower drug usage and reduction in drug-resistance development. An excellent example of a naturally derived and common dietary agent is curcumin, the active constituent of turmeric. Curcumin is known to modulate several signalling pathways in addition to displaying a diverse range of anti-tumour activities against a number of cancer cells. Several reports point to curcumin being beneficial if used in addition to chemotherapeutic drugs. In this study, synthetic aminonaphthoquinone derivatives (coded Rau 008, Rau 010, Rau 015 and Rau 018) were tested individually and in combination with curcumin for the potential as anti-breast cancer agents in different tumour cell lines. Notably, the aminonaphthoquinone class of compounds have shown potential as anti-cancer agents in various tumour cell lines. This study was thus aimed at screening the Rau compounds (and selected combinations with curcumin) for anti-cancer activity using a range of in vitro biological assays, and was not mechanistic in nature. The IC50 values of the individual and combined drugs were determined from dose-response curves using non-linear regression analyses. Synergistic, additive and antagonistic drug interactions were assessed using combination index and isobologram approaches. Based on these interactions, selected drug combinations were then further analysed for their potential anti-estrogenic, cytotoxic, anti-angiogenic and anti-metastatic effects against the ER(-) MDA-MB-231 and ER(+) MCF-7 breast cancer cell lines. The potential anti-cancer effects of the selected drug combinations on other estrogen-responsive models, such as the osteosarcoma (MG-63) and endometrial cancer (HEC-1A) cell lines, were also investigated. Overall, the findings of this study indicated that the sensitivity of the tumour cells to the various test compounds was significantly enhanced when combined with curcumin. For instance, in the presence of curcumin, Rau 008 or Rau 010 reduced the metastatic capability of ER(-) breast cancer cells significantly. The anti-proliferative effect of the Rau 015+curcumin combination was enhanced in ER(+) and ER(-) breast cancer, including oteosarcoma cells, while a combination of Rau 015 and curcumin induced a significant cytotoxic effect in ER(-) breast cancer and endometrial cancer-derived cells. A combination of Rau 018 and curcumin inhibited the proliferation of ER(+) breast cancer, and the combined effect was significantly more enhanced compared to individual treatment. A similar effect was noted in osteosarcoma-derived cells. Further, the Rau 018+curcumin combination exerted a marked cytotoxic and anti-angiogenic effect in ER(-) breast cancer, osteosarcoma and endometrial cancer in addition to inhibiting the attachment of ER(-) breast cancer cells to collagen. Notably, curcumin enhanced the anti-proliferative effect of Tamoxifen in breast cancer (MCF-7 and MDA-MB-231), osteosarcoma and endometrial cancer, and also induced a significant cytotoxic effect against ER(+) breast cancer and osteosarcoma, whilst also reducing the invasive potential of ER(-) breast cancer. A combination of 17β-estradiol and curcumin induced a marked anti-proliferative effect in ER(+) and ER(-) breast cancer, reduced the adhesion of ER(-) breast cancer to laminin, and elicited a significant cytotoxic and anti-angiogenic effect against endometrial cancer. Notably all the selected combinations (except Rau 018 and curcumin) inhibited bone mineralization. These findings point to the vital influence of curcumin in the responsiveness of ER(+) and ER(-) tumours towards the relative test agents. Further, among the Rau+curcumin combinations tested in this study, the anti-cancer activity of Rau 015+curcumin and Rau 018+curcumin appeared to be the most effective in the different cell lines tested. Nonetheless, it appears that a combination of 30 μM Rau 018 with 100 μM curcumin may be more promising as an anti-breast cancer agent against ER(+) and perhaps triple negative breast cancer, and warrants further investigation.
- Format
- xxi, 287 leaves
- Format
- Publisher
- Nelson Mandela Metropolitan University
- Publisher
- Faculty of Science
- Language
- English
- Rights
- Nelson Mandela Metropolitan University
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NMU School of BioMolecular and Chemical Sciences
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