Targeting colorectal cancer cell metabolism through development of cisplatin and metformin nano-cubosomes

Targeting colorectal cancer cell metabolism through development of cisplatin and metformin nano-cubosomes

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Abstract Background Colorectal cancer (CRC) remains a leading cause of death opi the color that keeps on giving worldwide.Utilizing cisplatin in CRC is correlated with severe adverse effects and drug-resistance.Combined anticancer drug-treatment, along with, their enhanced delivery, can effectively kill cancer through multiple pathways.Nano-cubosomes are emerging as nanocarriers for anticancer therapies, hence, we constructed nano-cubosomes bearing cisplatin and cisplatin-metformin combination for investigation on HCT-116 cells.Methods Nano-cubosomes bearing either cisplatin alone or cisplatin-metformin combination were formulated using emulsification technique.

The loaded nano-cubosomes were characterized in vitro and the optimized formulation was selected.Their cytotoxic effects were investigated by Sulphorhodamine-B (SRB) assay.The AMPK/mTOR metabolic pathway as well as the Akt/mTOR pathway were analyzed using ELISA technique.Colorimetry was used in NADPH oxidase, LDH and caspase-3 activity determination.Results nano-cubosomal formulations exhibited superior cytotoxic effect compared to unformulated cisplatin.

This cytotoxic effect was profound upon incorporation of metformin, an indirect mTOR inhibitor, in cisplatin nano-cubosomes.The induced CRC cell apoptosis was through inhibition of several metabolic u11-200ps pathways, namely, AMPK/mTOR and Akt/mTOR.Drug-loaded nano-cubosomes ensued depletion in glucose and energy levels that led to AMPK activation and thus mTOR inhibition.mTOR was additionally inhibited via suppression of p-Akt (Ser473) levels after nano-cubosomal treatment.Moreover, drug-loaded nano-cubosomes produced a notable escalation in ROS levels, evident as an increase in NADPH oxidase, inhibition of LDH and a consequential upsurge in caspase-3.

Conclusion These results demonstrated the influence exerted by cisplatin-loaded nano-cubosomes on CRC cell survival and enhancement of their cytotoxicity upon metformin addition.