Novel spirooxindole based benzimidazole scaffold: In vitro, nanoformulation and in vivo studies on anticancer and antimetastatic activity of breast adenocarcinoma

The present work provided in vitro anticancer investigation of novel spirooxindole based benzimidazole scaffold SP1 and its nanoformulation with in vivo evaluation of anticancer and antimetastatic activity as potential drug for breast adenocarcinoma. The synthesized compound SP1 exhibited potent growth inhibitory efficacy against four types of human cancer (breast, prostate, colon and lung) cell lines with IC50 = 2.4, 3.4, 7.24 and 7.81 mu M and selectivity index 5.79, 4.08, 1.93 and 1.78 respectively. Flow cytometric analysis illustrated that SP1 exhibited high apoptotic effect on all tested cancer cell lines (38.22-52.3 %). The mode of action of this promising compound was declared by its ability to upregulate the gene expression of p21 (2.29-3.91 folds) with suppressing cyclin D (1.9-8.93 folds) and NF-.B (1.26-1.44 fold) in the treated cancer cells. Also, it enhanced the protein expression of apoptotic marker p53 and moderate binding affinity for MDM2 (KD;7.94 mu M). Notwithstanding these promising impressive findings, its selectivity against cancer cell lines and safety on normal cells were improved by nanoformulation. Therefore, SP1 was formulated as ultra-flexible niosomal nanovesicles (transethoniosomes). The ultra-deformability is attributable to the synergism between ethanol and edge activators in improving the flexibility of the nanovesicular membrane. F8 exhibited high deformability index (DI) of (23.48 +/- 1.4). It was found that % SP1 released from the optimized transethoniosomal formula (F8) after 12 h (Q12h) was 84.17 +/- 1.29 % and its entrapment efficiency (%EE) was 76.48 +/- 1.44 %. Based upon the very encouraging and promising in vitro results, an in vivo study was carried out in female Balb/c mice weighing (15-25 g). SP1 did halt the proliferation of breast cancer cells as well as suppressed the metastasis in other organs like liver, lung and heart.

Automated summary

This study investigated the anticancer activity of the compound SP1 and its nanoformulation against breast adenocarcinoma. The results showed that SP1 exhibited strong inhibitory effects on multiple cancer cell lines and induced apoptosis. The use of a nanoformulation improved the selectivity of the compound against cancer cells. In vivo studies on mice confirmed the ability of SP1 to halt the proliferation of breast cancer cells and suppress metastasis.