Chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells

Abstract

Cyclotides comprise a family of circular mini-peptides that have been isolated from various plants and have a wide range of bioactivities. Previous studies have demonstrated that cyclotides have antitumor effects and cause cell death by membrane permeabilization. The present study aimed to evaluate the cytotoxicity and chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells. In this study, a total of seven cyclotides were selected for colorimetric cell viability assay (MTT assay) to evaluate their anticancer and chemosensitizing activities in the lung cancer cell line A549 and its sub-line A549/paclitaxel. Results suggested that certain cyclotides had significant anticancer and chemosensitizing abilities; such cyclotides were capable of causing multi-fold decreases in the half maximal inhibitory concentration (IC50) value of cliotides in the presence of paclitaxel. More importantly, their bioactivities were found to be correlated with their net charge status. In conclusion, cyclotides from C. ternatea have potential in chemosensitization application.

Current scenario of peptide-based drugs: the key roles of cationic antitumor and antiviral peptides

“…A study carried out by Sen et al (2013) has isolated five cyclotides named CT2, CT4, CT7, CT10, and CT12 (with an addition or removal of a net charge from −1 to +2) from this plant species. They showed significant cytotoxicity against human lung cancer cells (A549) and demonstrated a reduction of 2- to 4-fold of the IC 50 (half maximal inhibitory concentration) value of cyclotides when compared to a mitotic inhibitor used in cancer chemotherapy.…”

“…They showed significant cytotoxicity against human lung cancer cells (A549) and demonstrated a reduction of 2- to 4-fold of the IC 50 (half maximal inhibitory concentration) value of cyclotides when compared to a mitotic inhibitor used in cancer chemotherapy. Moreover, these peptides were less cytotoxic against A549/paclitaxel (a sub-linage of A594) than only A549, which demonstrates a possible use of chemo-sensitization for treating cancer (Sen et al, 2013). …”

Anionic Host Defence Peptides from the Plant Kingdom: Their Anticancer Activity and Mechanisms of Action

“…More recently, cliotide CT2 was found to have activity against human nonsmall lung cancer cells (A549; IC 50 = 7.6 μM) and an A549-derived paclitaxel-resistant sub-line (A549/taxol; IC 50 = 7.9 μM). However, in the case of A549/taxol cells this IC 50 was reduced to 1.62 μM when these cells were exposed to 50:50 ratios of cliotide CT2 and paclitaxel [68], which is another well-established anticancer drug [69]. These observations indicated a synergistic action between paclitaxel and cliotide CT2 and showed that the peptide was able to chemosensitize cancer cells to conventional anticancer drugs [68].…”

“…For example, PE shows the potential to serve as a biomarker for many malignancies [98] and it has been proposed that derivatives of PE-binding cyclotides may be suitable for development as agents in tumour imaging and anticancer therapeutics [75,76,81,99,100]. As another example, it may be possible to optimise the membrane-permeabilizing ability of cyclotides through scaffold modification to efficiently synergise the action of established anticancer drugs, as described above for cliotide CT2 and paclitaxel [68]. Proof-of-concept for such work was recently demonstrated when a grafted cyclotide, showed activity against growth factors involved in angiogenesis [101]; it is well-established that tumor growth is usually associated with unregulated angiogenesis [102].…”

“…However, in the case of A549/taxol cells this IC 50 was reduced to 1.62 μM when these cells were exposed to 50:50 ratios of cliotide CT2 and paclitaxel [68], which is another well-established anticancer drug [69]. These observations indicated a synergistic action between paclitaxel and cliotide CT2 and showed that the peptide was able to chemosensitize cancer cells to conventional anticancer drugs [68]. A similar chemosensitizing ability has been demonstrated for a number of other cyclotides in combination with doxorubicin and it was suggested that this synergistic interaction resulted from the ability of cyclotides to disrupt cellular membranes, thereby allowed increased uptake of doxorubicin into drug resistant cells [70].…”