Abstract
Cell-penetrating peptides (CPPs) are highly promising tools to deliver therapeutic molecules into tumours. αVβ3 integrins are cell–matrix adhesion receptors, and are considered as an attractive target for anticancer therapies owing to their roles in the process of metastasis and angiogenesis. Therefore, this study aims to assess the effect of co-administration of zerumbone (ZER) and ZERencapsulated in hydroxypropyl-β-cyclodextrin with TP5-iRGD peptide towards cell cytotoxicity, apoptosis induction, and proliferation of normal and cancerous breast cells utilizing in vitro assays, as well as to study the molecular docking of ZER in complex with TP5-iRGD peptide. Cell viability assay findings indicated that ZER and ZERencapsulated in hydroxypropyl-β-cyclodextrin (ZER-HPβCD) inhibited the growth of estrogen receptor positivebreast cancer cells (ER+ MCF-7) at 72 h treatment with an inhibitory concentration (IC)50 of 7.51 ± 0.2 and 5.08 ± 0.2 µg/mL, respectively, and inhibited the growth of triple negative breast cancer cells (MDA-MB-231) with an IC50 of 14.96 ± 1.52 µg/mL and 12.18 ± 0.7 µg/mL, respectively. On the other hand, TP5-iRGD peptide showed no significant cytotoxicity on both cancer and normal cells. Interestingly, co-administration of TP5-iRGD peptide in MCF-7 cells reduced the IC50 of ZER from 7.51 ± 0.2 µg/mL to 3.13 ± 0.7 µg/mL and reduced the IC50 of ZER-HPβCD from 5.08 ± 0.2 µg/mL to 0.49 ± 0.004 µg/mL, indicating that the co-administration enhances the potency and increases the efficacy of ZER and ZER-HPβCD compounds. Acridine orange (AO)/propidium iodide (PI) staining under fluorescence microscopy showed evidence of early apoptosis after 72 h from the co-administration of ZER or ZER-HPβCD with TP5-iRGD peptide in MCF-7 breast cancer cells. The findings of the computational modelling experiment provide novel insights into the ZER interaction with integrin αvβ3 in the presence of TP5-iRGD, and this could explain why ZER has better antitumor activities when co-administered with TP5-iRGD peptide.
Highlights
Breast cancer, with an estimated 2.1 million newly diagnosed cases in 2018, is considered as the most prevalent cancer, eliciting a high mortality rate among women worldwide [1]
The cytotoxicity of ZER, ZER-HPβCD, and TP5-iRGD peptide was investigated in MCF-7, MDA-MB-231, and Hs27 at different time points
In this we demonstrated that the in vitro anticancer activity of ZER against breast cancer cells could be study, we demonstrated that the in vitro anticancer activity of ZER against breast cancer cells could enhanced upon co-administration with TP5-iRGD peptide by inducing apoptosis
Summary
With an estimated 2.1 million newly diagnosed cases in 2018, is considered as the most prevalent cancer, eliciting a high mortality rate among women worldwide [1]. Poor penetrability of anticancer drugs into tumors is considered as an important factor limiting their efficacy. Many antineoplastic drugs invade only three to five cell diameters deep from the blood vessels, leading to reduced efficacy as well as the development of drug resistance [3,4]. Acquired resistance to chemotherapy thwarts the efficient treatment of the patients. Owing to these limitations, improving the efficacy and permeability of chemotherapeutic agents is an urgent requirement [5,6]. Several therapeutic options are available for the treatment of cancers, including breast cancer; none of them completely suppress the tumour metastases or disease progression. There is a definite need for new therapeutic development approaches, such as peptide-drug conjugates for cancer targeting therapy [7]
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