Abstract:
Breast cancer stem cells (BCSCs), as a subset of cancer cells with enriched capacity
to generate breast tumors, have recently been attributed to driving cancer recurrence
and metastasis. Although the importance of developing strategies to target BCSCs has
been 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 either of these possibilities
would confound the effectiveness of therapeutic agents that exclusively target BCSCs,
this study aimed to develop combinatory therapeutics that apply agents targeting both
BCSCs and non-BCSCs. By utilising parental cells and mammospheres as screening
platforms, a total of 193 candidate molecules were identified as potent hit compounds
inhibiting both BCSCs and non-BCSCs. Subsequent analysis suggested histone
deacetylase (HDAC) inhibitors as a class of anti-cancer 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, against BCSCs and non-BCSCs derived from MDA-MB-
468; whereas their combined treatment with anti-mitotic chemotherapy, namely
paclitaxel, only exerted synergy in MDA-MB-468 non-BCSCs. Intriguingly, neither pan-HDAC, hydroxamate-based inhibitor nor class I specific, benzamide-based
HDAC inhibitor was superior to be combined with conventional chemotherapeutics
against these BCSCs and non-BCSCs. Further evaluations indicated that quisinostat,
as the most potent HDAC inhibitor tested, managed to enhance the doxorubicininduced
cytotoxicity in both BCSCs and non-BCSCs derived from different subtypes,
including basal-like triple negative breast cancer (TNBC) subtypes (MDA-MB-468
and HCC38), mesenchymal-like TNBC (MDA-MB-231), and luminal-like breast
cancer (MCF-7). Conversely, the synergism between quisinostat and cisplatin was
TNBC subtype-dependent. Also, it was observed that both BCSCs and non-BCSCs
of TNBC subtypes were more sensitive to the co-treatment of quisinostat with DNA damaging chemotherapeutics, as compared to luminal-like breast cancer subtype.
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.
In summary, this study offered HDAC inhibitors as novel therapeutic options, either
as monotherapy or combination therapy, for refractory breast cancer treatment which
warrants detailed investigations.
