Synergistic Cytotoxic and Antimigratory Effect of Brazilein and Doxorubicin on HER2-Overexpressing Cells

Abstract

Objective:The present research aims to report cytotoxic and antimigratory activities of the oxidized form of brazilin, i.e., brazilein, and the effects of the combination of brazilein-doxorubicin on MCF-7/HER2 cells. Methods: The MTT assay was conducted to test the cytotoxic activity, while flow cytometry with PI and PI-annexin V staining were respectively performed for cell cycle and apoptosis analyses. Migration and invasion analyses were assessed via Boyden chamber assay, while HER2, Rac1, p120, MMP2, and MMP9 protein levels were determined by immunoblotting and gelatin zymography. Molecular docking of ligands with HER2, Src, PI3Kα, PI3KΔ, and PI3Kγ proteins was evaluated using MOE 2010. Results: The MTT assay showed that the IC 50 value of brazilein against MCF-7/HER2 cells was 51 ± 2.1 µM. Moreover, brazilein and its combination with doxorubicin-induced G2/M accumulation and apoptosis. Combination of brazilein-doxorubicin inhibited cell migration and tended to decrease HER2, Rac1, p120, MMP2, and MMP9 protein expression levels. Based on our molecular docking study, the docking score of brazilein with PI3Kγ is comparable to that of the native ligand. Conclusion: Taken together, a combination of brazilein-doxorubicin exhibited synergistic cytotoxic and antimigratory effects on MCF-7/HER2 cells.

Comparative Studies of Resveratrol, Oxyresveratrol and Dihydrooxyresveratrol on Doxorubicin-Treated Lung Cancer Cells

“…Based on previous cancer studies about the correlation between high MMP2 and MMP9 and metastasis, Oxy-RES can induce DOX to achieve higher metastatic inhibition than DOX alone and DOX with RES or DHoxy -RES. Synergistic effect of suppression of MMP2 and MMP9 might be possible to increase DOX activity as found in combination of brazilein and DOX [ 54 , 55 ]. This should be the benefit of RES analog, especially Oxy-RES, for cancer therapy both primary and metastatic mass as found in p53 and SIRT1 expressions.…”

“…This should be the reason of higher activity to cancer cells of Oxy-RES than RES. Moreover, the higher water solubility of Oxy-RES (more than 0.1 mg/ml) than RES (0.05 mg/ml) [ 55 ] (manufacturer instruction) can imply to higher bioavailability leading to higher therapeutic activity. For DHoxy-RES, its molecular structure with single bond at the center of molecule may be the cause of less contact to polar head of phospholipid and lead to low antimetastatic activity to cancer cells.…”

Caesalpinia sappan reduces the stemness of breast cancer stem cells involving the elevation of intracellular reactive oxygen species

“…Therefore, CSE has been suggested as a potential anticancer agent with the advantage of low side effects ( 13 14 15 ). CSE was also demonstrated to have strong cytotoxic activity on human epidermal growth receptor-2-positive breast cancer cells by blocking NF-κB activation and reducing MMP2 protein levels ( 16 ). These activities are mediated by cell cycle inhibition, apoptosis induction, and migration inhibition ( 15 ).…”

“…These activities are mediated by cell cycle inhibition, apoptosis induction, and migration inhibition ( 15 ). CSE induces apoptosis by inhibiting reactive oxygen species (ROS) generation and anti-apoptosis protein expression ( 11 12 16 ). Moreover, co-administration of brazilin and brazilein with conventional chemotherapeutic drugs may result in stronger anticancer effects at non-toxic quantities of these substances ( 16 ).…”

“…CSE induces apoptosis by inhibiting reactive oxygen species (ROS) generation and anti-apoptosis protein expression ( 11 12 16 ). Moreover, co-administration of brazilin and brazilein with conventional chemotherapeutic drugs may result in stronger anticancer effects at non-toxic quantities of these substances ( 16 ). Considering the significance of BCSCs and the need to specifically target this subset of tumor cells, this study aimed to assess how CSE affected the cytotoxicity, cell cycle distribution, apoptosis induction, and ROS production of MDA-MB-231 and its isolated CD44+/CD24-BCSCs.…”