Triple-Negative Breast Cancer Cells Exhibit DifferentialSensitivity to Cardenolides from Calotropis gigantea
2020
Triple-negative breast cancers (TNBC)
are aggressive and heterogeneous
cancers that lack targeted therapies. We implemented a screening program
to identify new leads for subgroups of TNBC using diverse cell lines
with different molecular drivers. Through this program, we identified
an extract from Calotropis gigantea that caused selective
cytotoxicity in BT-549 cells as compared to four other TNBC cell lines.
Bioassay-guided fractionation of the BT-549 selective extract yielded
nine cardenolides responsible for the selective activity. These included
eight known cardenolides and a new cardenolide glycoside. Structure–activity
relationships among the cardenolides demonstrated a correlation between
their relative potencies toward BT-549 cells and Na+/K+ ATPase inhibition. Calotropin, the compound with the highest
degree of selectivity for BT-549 cells, increased intracellular
Ca2+ in sensitive cells to a greater extent than in the
resistant MDA-MB-231 cells. Further studies identified a second TNBC
cell line, Hs578T, that is also highly sensitive to the cardenolides,
and mechanistic studies were conducted to identify commonalities among
the sensitive cell lines. Experiments showed that both cardenolide-sensitive
cell lines expressed higher mRNA levels of the Na+/Ca2+ exchanger NCX1 than resistant TNBC cells. This suggests
that NCX1 could be a biomarker to identify TNBC patients that might
benefit from the clinical administration of a cardiac glycoside for
anticancer indications.
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