Cisplatin and Metformin nano-cubosomes demonstrate higher cytotoxicity in CRC than individual drugs

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Mona M Saber, Abdulaziz M Al-mahallawi, Noha N Nassar and Samia A Shouman

Cairo University, Egypt

: J Nephrol Ren Dis

Abstract

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Colorectal cancer (CRC) remains a leading cause of death worldwide. The use of cisplatin as an anticancer drug in CRC is correlated with severe adverse effects and drug resistance. Utilizing combination of anticancer agents can effectively kill cancer through multiple pathways; nonetheless, improvements in their delivery are needed. Nano-cubosomes, thanks to the advantages of their liquid crystalline porous nanoarchitecture and capability for multi-drug encapsulation, appear to be of interest as nanocarriers for anticancer therapies. Hence, delivering cisplatin, as nanocubosomes, concomitantly with other chemo-dugs can lead to a rationally designed therapy for chemo-resistant cancers and might overcome problems associated with conventional cisplatin treatment. Therefore, we constructed nano-cubosomes bearing either cisplatin alone or cisplatin-metformin combination that are able to enhance drug transport to HCT-116 CRC cells. Results from this study revealed that nano-cubosomal formulations exhibited superior cytotoxic effect compared to unformulated cisplatin. This cytotoxic effect was profound upon incorporation of metformin, an 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 levels after nano-cubosomal treatment. Moreover, drugloaded 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. These results demonstrated the influence exerted by cisplatin-loaded nano-cubosomes on CRC cell survival and enhancement of their cytotoxicity upon metformin addition.

Biography

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Mona M Saber has completed her PhD from Cairo University in 2018. Currently, she is a lecturer at the Pharmacology and Toxicology department, of a premier research organization. She has published 2 articles related to colorectal cancer in the BMC Cancer journal. She spent 6 months in the institute of molecular medicine in Heinrich Heine University, Dusseldorf, Germany. This was a German Egyptian Research Short term scholarship funded by the DAAD (Deutscher Akademischer Austauchdienst). She has attended several international and national conferences including but not limited to; European cancer congress (ESMO 2015), 12th and 13th congress of EACPT, 2016 and 2017 conference of BGICC.

E-mail: mona.magdy@pharma.cu.edu.eg