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Open Access
Combination treatment with EGFR inhibitor and doxorubicin synergistically inhibits proliferation of MCF-7 cells and MDA-MB-231 triple-negative breast cancer cells In Vitro
(MDPI, 2024) Abrahams, Beynon; Gerber, Anthonie; Hiss, Donavon C.
The role of the epidermal growth factor receptor (EGFR) in tumor progression and survival is often underplayed. Its expression and/or dysregulation is associated with disease advancement and poor patient outcome as well as drug resistance in breast cancer. EGFR is often overexpressed in breast cancer and particularly triple-negative breast cancer (TNBC), which currently lacks molecular targets. We examined the synergistic potential of an EGFR inhibitor (EGFRi) in combination with doxorubicin (Dox) in estrogen-positive (ER+) MCF-7 and MDA-MB-231 TNBC cell lines. The exposure of MDA-MB-231 and MCF-7 to EGFRi produced an IC₅₀ₛ of 6.03 µM and 3.96 µM, respectively. Dox induced MDA-MB-231 (IC₅₀ 9.67 µM) and MCF-7 (IC₅₀ 1.4 µM) cytotoxicity. Combinations of EGFRi-Dox significantly reduced the IC₅₀ in MCF-7 (0.46 µM) and MBA-MB 231 (0.01 µM). Synergistic drug interactions in both cell lines were confirmed using the Bliss independence model. Pro-apoptotic Caspase-3/7 activation occurred in MCF-7 at 0.1–10 µM of EGFRi and Dox single treatments, whilst 1 μM Dox yielded a more potent effect on MDA-MB-231. EGFRi and Dox individually and in combination downregulated the EGFR gene expression in MCF-7 and MDA-MB-231 (p < 0.001). This study demonstrates EGFRi’s potential for eliciting synergistic interactions with Dox, causing enhanced growth inhibition, apoptosis induction, and downregulation of EGFR in both cell lines.
Open Access
Establishing a cisplatin-resistant triple negative breast cancer spheroid model
(University of the Free State, 2024) Ngalonkulu, Ongeziwe; Sekhoacha, Mamello; Abrahams, Beynon; Gouws, Chrisna
In cancer research, conventional two-dimensional (2D) cell cultures and animal studies are often used in studying the disease and efficacy of anticancer agents despite their failure to accurately replicate the complex 𝘪𝘯 𝘷𝘪𝘷𝘰 tumour microenvironment. 2D cultures lack the extracellular matrix production critical for 𝘪𝘯 𝘷𝘪𝘷𝘰-like cell behaviour, thereby jeopardizing data accuracy when developing effective cancer therapies and understanding mechanisms underlying drug resistance and cancer relapse. There is, therefore, a pressing need for models that accurately recapitulate 𝘪𝘯 𝘷𝘪𝘷𝘰 systems and enhance researchers’ accuracy in predicting disease mechanisms. This study aimed to establish a cisplatin-resistant three-dimensional (3D) spheroid model using the scaffold-free technique of rotating wall bioreactors in the CelVivo ClinoStar™ system, to facilitate efficient recapitulation of 𝘪𝘯 𝘷𝘪𝘷𝘰-like conditions and higher throughput. The MDA-MB-231 cell line is classified as triple negative breast cancer (TNBC) due to the absence of the oestrogen receptor and progesterone receptor, as well as the human epidermal growth factor receptor 2. As a result, the MDA-MB-231 cell line is characterized as a highly metastatic and aggressive cell line with a poor prognosis. Cisplatin-resistant MDA-MB-231 cells were generated by exposing the cell line to IC10-IC50 (0.01μM, 0.1μM, 1μM, 5μM and 10μM) concentrations of cisplatin for nine months. The cells acquired resistance; these resistant cells were then used to develop a 3D spheroid model. Characterization of the cisplatin-resistant MDA-MB-231 spheroids over 28 days included assessing spheroid growth and viability, and identifying the optimal experimental window between days 12 and 22. The model's reactivity to cisplatin and doxorubicin treatment was evaluated for 96 hour (h) to qualify the model for treatment screening. Treatment with the clinical cisplatin dose (4,435 x 10⁻⁶ μg cisplatin/μg protein) showed pronounced reactivity after 48 h, with decreased cell viability and increased cell death. However, spheroids recovered after 72-96 h, displaying moderate to high metabolic activity, typical of resistance. The IC₅₀ (8.06 x 10⁻² μg cisplatin/μg protein) dose of cisplatin demonstrated immediate effects on the model after 48 h, however, increase in spheroid size and decrease in cell death was observed with increased metabolic activity after apparent recovery at 72-96 h suggesting resistance. Treatment with doxorubicin clinical dose (1.064 x 10⁻⁵ μg dox/μg protein) had the most pronounced effect on the model throughout the 96 h and resulted in decreased spheroid size. It was apparent that the model was not as resistant to the doxorubicin treatment as it was to the cisplatin treatment. This model has potential for preclinical research studies as it displays reactivity to commonly used chemotherapeutic drugs and could be valuable in understanding drug-resistant cancer. In conclusion, the established cisplatin-resistant MDA-MB-231 3D spheroid model offers a robust platform for studying drug effects in TNBC research.
Open Access
Investigating the potential antiproliferative effect of 𝘔𝘰𝘳𝘪𝘯𝘨𝘢 𝘰𝘭𝘦𝘪𝘧𝘦𝘳𝘢 aqueous leaf extract in MCF-7 breast cancer cells
(University of the Free State, 2023) Moremane, Malebogo M.; Tiloke, Charlette; Abrahams, Beynon
𝗕𝗮𝗰𝗸𝗴𝗿𝗼𝘂𝗻𝗱: Breast cancer is associated with elevated mortality and morbidity rates in women across the world. Current chemotherapeutic drugs such as Doxorubicin (Dox) display contra-indications, thus expressing the need for alternative treatment methods. Therefore, to reduce the cancer burden, the study’s objective was to investigate whether an aqueous leaf extract of 𝘔𝘰𝘳𝘪𝘯𝘨𝘢 𝘰𝘭𝘦𝘪𝘧𝘦𝘳𝘢 (MO), a medicinal tree native to India and indigenous to Africa, possesses antiproliferative potential against MCF-7 breast cancer cells. 𝗠𝗲𝘁𝗵𝗼𝗱𝗼𝗹𝗼𝗴𝘆: In order to suppress cell growth, MCF-7 cells were treated with MO (2600 μg/ml) for 72 hours. Cells were also co-exposed with Dox (0.978 μM), modelled as a positive control. The unexposed cells served as the control. Biochemical analysis was conducted after 72 hours (MTT, GSH, DCFH-DA, ATP, Caspase 3/7, 8/9, qPCR and western blot assays) to assess the efficacy of MO and Dox. 𝗥𝗲𝘀𝘂𝗹𝘁𝘀: 𝘔𝘰𝘳𝘪𝘯𝘨𝘢 𝘰𝘭𝘦𝘪𝘧𝘦𝘳𝘢 aqueous leaf extract significantly reduced the proliferation of breast cancer cells by inducing oxidative stress through increasing ROS whilst decreasing glutathione content and Nrf2 protein expression. Additionally, MO induced apoptosis by increasing caspases -3/7, -8, -9, metabolic activity and upregulating p53. Similar results were observed in Dox-exposed cells. Furthermore, cell death due to MO was activated with downregulation of Bcl-2, PARP-1 and Bax. Dox decreased the growth of breast cancer cells by increasing ROS. In contrast, Dox induced chemoresistance through increased GSH content and downregulated apoptotic protein Bax and p53 gene. However, the MO + Dox combination induced antiproliferative potential similarly to MO, suggesting a possible synergistic effect. 𝗖𝗼𝗻𝗰𝗹𝘂𝘀𝗶𝗼𝗻: MO aqueous leaf extract displayed antiproliferative potential by inducing apoptosis and oxidative damage to the MCF-7 breast cancer cells
Open Access
Moringa oleifera: a review on the antiproliferative potential in breast cancer cells
(MDPI, 2023) Moremane, Malebogo M.; Abrahams, Beynon; Tiloke, Charlette
The global burden of female breast cancer and associated deaths has become a major concern. Many chemotherapeutic agents, such as doxorubicin, have been shown to have adverse side effects. The development of multi-drug resistance is a common occurrence, contributing to chemotherapeutic failure. The resistance of breast cancer cells to drug treatment leads to a decline in the treatment efficacy and an increase in cancer recurrence. Therefore, action is required to produce alternative drug therapies, such as herbal drugs. Herbal drugs have been proven to be beneficial in treating illnesses, including cancer. This review aims to highlight the antiproliferative potential of Moringa oleifera (MO), a medicinal tree native to India and indigenous to Africa, in breast cancer cells. Although MO is not yet considered a commercial chemopreventive drug, previous studies have indicated that it could become a chemotherapeutic agent. The possible antiproliferative potential of MO aqueous leaf extract has been previously proven through its antioxidant potential as well as its ability to induce apoptosis. This review will provide an increased understanding of the effect that MO aqueous leaf extract could potentially have against breast cancer.

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