An ingenious non-spherical mesoporous silica nanoparticle cargo with curcumin induces mitochondria-mediated apoptosis in breast cancer (MCF-7) cells
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Lakshminarasimhan Harini1, Sweta Srivastava2, George Peter Gnanakumar3, Bose Karthikeyan1,4, Cecil Ross5, Vaithilingam Krishnakumar6, Velu Rajesh Kannan6, Krishnan Sundar1,7 and Thandavarayan Kathiresan1,7
1Department of Biotechnology, Kalasalingam University, Krishnankoil, Tamil Nadu, India
2Department of Translation Medicine, St. Johns National Academy of Health Sciences, Bangalore, Karnataka, India
3School of Physical Chemistry, Madurai Kamaraj University, Madurai, Tamil Nadu, India
4Oregon Health and Science University, Knight Cardiovascular Institute (KCVI), Portland, Oregon, USA
5Department of Medicine, St. Johns National Academy of Health Sciences, Bangalore, Karnataka, India
6Department of Microbiology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
7International Research Centre, Kalasalingam University, Krishnankoil, Tamil Nadu, India
Thandavarayan Kathiresan, email: [email protected]
Keywords: caspase; mesoporous silica nanoparticle; toxicity; mitochondria; doxorubicin
Received: July 25, 2018 Accepted: January 12, 2019 Published: February 05, 2019
Curcumin delivery to cancer cells is challenging due to its hydrophobic nature, low bio distribution and low availability. Many nano vehicles suffer from low stability and toxicity, and hence the prerequisite of a non-toxic nano vehicle with effective drug delivery is still being delved. The present study investigates the delivery efficiency of curcumin with non-spherical mesoporous silica nanoparticles (MSNAs). Their mechanism of drug delivery and signalling proteins activated to induce apoptosis was further explored in MCF-7 cells. A non-spherical MSN was synthesised, functionalised with PEI (MSNAP) and analysed its intracellular behaviour. Our result indicates that MSNAP was non-toxic until 20 μg/mL and likely localizes in cytoplasmic vesicles. On contrast, well-known MCM-41P induced autophagosome formation, indicating cellular toxicity. Curcumin was loaded on MSNAP and its effectiveness in inducing cell death was studied in MCF-7 and in MCF-7R cells. Curcumin loading on MSNAP induces better cell death with 30 μM curcumin, better than unbounded curcumin. Western blot analysis suggest, curcumin induce apoptosis through the activation of caspase 9, 6, 12, PARP, CHOP and PTEN. The cell survival protein Akt1 was downregulated by curcumin with and without the nanostructure. Interestingly, cleaved caspase 9 was activated in higher amount in nano-conjugated curcumin compared to the free curcumin. But other ER resident protein like IRE1α, PERK and GRP78 were downregulated indicating curcumin disturbs ER homeostasis. Further, electron microscopic analysis reveled that nanocurcumin induced apoptosis by disrupting mitochondria and nucleus. Our results with doxorubicin resistant MCF-7 cell lines confirm nanodelivery of doxorubicin and curcumin sensitised cells effectively at lesser concentration. Further docking studies of curcumin indicate it interacts with the apoptotic proteins through hydrogen bonding formation and with higher binding energy.
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