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

Abstract

BackgroundColorectal cancer (CRC) remains a leading cause of death 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.MethodsNano-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.Resultsnano-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 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.ConclusionThese results demonstrated the influence exerted by cisplatin-loaded nano-cubosomes on CRC cell survival and enhancement of their cytotoxicity upon metformin addition.

<p>Antitumor Activity of Cabazitaxel and MSC-TRAIL Derived Extracellular Vesicles in Drug-Resistant Oral Squamous Cell Carcinoma</p>

“…This phenomenon is consistent with previous studies, such as those on gemcitabine and paclitaxel loaded in mesoporous silicon 41 and cisplatin and metformin-loaded nanocubes. 42 Both groups showed higher cytotoxicity or apoptosis induction than the free drug group. In addition to the abovementioned reasons in vitro, the high efficiency in vivo could also be attributed to the cell-homing effect of EXO derived from mesenchymal stem cells and the short half-life of the hydrophobic drug CTX in vivo.…”

Recent progress in nanotechnology-based novel drug delivery systems in designing of cisplatin for cancer therapy: an overview

“…Cubosomes are classified under lipid-based nanostructured carrier, having the size of between 100 and 300 nm; cubosomes displayed large surface area and low viscosity [94]. This strategy was utilized for the co-delivery of cisplatin with metformin via the emulsification technique.…”

“…Meanwhile, cubosomes had enhanced their cytotoxicity based on the addition of metformin. This novel cubosomes-based formulation exaggerated different intracellular targets with efficient inhibition effect on tumour linked with different metabolic pathways leading to enhanced the apoptosis [94].…”

Nephroprotection and chemotherapy sensitivity impact of metformin during cisplatin therapy; an updated review

“…Nano-cubosomal metformin-cisplatin combination enhances cytotoxic efficiency in colorectal cancer cells compared to unformulated cisplatin through inhibition of AMPK/mTOR and AKT /mTOR pathways due to additional mTOR inhibitors (metformin) and energy depletion. Moreover, drug-loaded nano-cubosomes cause a substantial intensification in ROS levels, NADPH oxidase, lactate dehydrogenase inhibition, and a significant increase in caspase-3 (34).…”