Cycloviolacin O2 (CyO2), a
cyclotide from Viola odorata (Violaceae) has antitumor effects and causes cell death by membrane permeabilization. In the
breast cancer line, MCF-7 and its
drug resistant subline MCF-7/ADR, the cytotoxic effects of CyO2 (0.2-10 microM) were monitored in the presence and absence of
doxorubicin (0.1-5 microM) using cell proliferation assays to establish its chemosensitizing abilities.
SYTOX Green assays were Sperformed to verify membrane permeabilization and showed cellular disruption correlates with
cyclotide chemosensitization. Fluorescence microscopy studies demonstrated increased cellular internalization of
doxorubicin in
drug resistant cells when coexposed to CyO2. Interestingly, CyO2 did not produce significant membrane disruption in primary human brain endothelial cells, which suggested
cyclotide specificity toward induced pore formation in highly proliferating
tumor cells. Furthermore, three novel
cyclotides (
psyle A, C and E) from Psychotria leptothyrsa (Rubiaceae) were also monitored for cytotoxic activity. The
cyclotides displayed potent cytotoxicity (IC50 = 0.64->10 microM), and coexposure to
cyclotides significantly enhanced
doxorubicin induced toxicity (IC50 = 0.39-0.76 microM). This study documents several
cyclotides with robust cytotoxicity that may be promising chemosensitizing agents against
drug resistant
breast cancer.