{'fraction_non_alphanumeric': 0.021334367726920093, 'fraction_numerical': 0.0034910783553141972, 'mean_word_length': 5.804749340369393, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Identification of Inhibitors Synergizing Chemotherapeutic Sensitivity in the Breast Cancer Stem Cells and Non-Stem Breast Cancer Cells

Background: Breast cancer stem cells (BCSCs), as a subset of cancer cells with enriched capacity to generate breast tumors, have recently been attributed to driving chemoresistance, cancer recurrence and metastasis. Although the importance of developing strategies to target BCSCs has been recently highlighted, it is conceivable that the depletion of BCSCs within a breast tumor would not lead to complete regression since non-BCSCs might still be capable of sustaining tumor growth or regaining BCSC potential. As conventional chemotherapeutics have been well-established and known to eradicate non-BCSCs, potentially it is preferable to develop BCSC-targeting agents in combination with chemotherapy, to overcome any of the possibilities that would confound the effectiveness of therapeutic agents that exclusively target BCSCs. Aim: This study aimed to rapidly identify and develop BCSC-targeting agents that could pair synergistically with conventional chemotherapeutic agents to produce desired tumor-specific cell death in both BCSCs and non-BCSCs. Methods: By exploiting the capability of enriching BCSCs from breast cancer cell lines, we performed high-throughput screening of a well-characterized chemical library consisting of 1672 diverse bioactive small molecules to identify agents that effective against BCSCs and non-BCSCs. The candidate hit molecules were then paired with chemotherapeutic agents to evaluate the drug combinatory effects on BCSCs and non-BCSCs. Results: Through our comprehensive chemical library screening against BCSCs and non-BCSCs, we identified a total of 193 candidate molecules, including 45 FDA approved drugs, which could target both BCSCs and non-BCSCs. Subsequent analysis suggested histone deacetylase (HDAC) inhibitors as a potential class of anticancer agents targeting both BCSCs and non-BCSCs. When combined with conventional chemotherapeutics, HDAC inhibitors were found to synergise DNA-damaging chemotherapeutics, namely doxorubicin and cisplatin, in killing both BCSCs and non-BCSCs. Moreover, the dose reduction potentials of these combinatory regimens that revealed in this study may be exploited to reduce the dose-limited toxicities in clinical oncology. Conclusion: In summary, our data suggests that HDAC inhibitors represent a class of therapeutic options, either as monotherapy or combination therapy, for refractory breast cancer treatment which warrants detailed investigations.