Surface modified PAMAM dendrimers with gallic acid inhibit, cell proliferation, cell migration and inflammatory response to augment apoptotic cell death in human colon carcinoma cells

Abstract

To overcome the obstacle of anti-cancer therapy significant attention has been drawn for improving drug delivery system. Since recent past, different approaches were applied using synthetic or natural derivatives for improving efficacy of anti-cancer drugs in cancer therapeutics. Gallic acid (GA) is a natural polyphenol, which exhibits a broad spectrum of biological activities, but its therapeutic application was limited due to poor bioavailability and toxicity. In the present study, we had conjugated the GA with PAMAM dendrimers and proposed the insights of molecular mechanism on inhibition of cell proliferation and programmed cell death through apoptotic pathway in human colon carcinoma cells. GA was chemically conjugated with 4.0 G PAMAM dendrimer at outer surface and characterized by different biophysical methods. We further examined its bioavailability, anti-cancer activity and explored the molecular mechanism of programmed cell death signaling in HCT116 cells. The results show that PAMAM-GA conjugate inhibits cell proliferation of different origin of cancer cells, improves cellular uptake of GA, inhibits colonogenic ability, restricts cancer cell migration by down regulating the expression of MMP-9, inhibits NF-kB activation and release of pro-inflammatory cytokines to manifest apoptotic cell death in HCT 116 cells rather than necrosis. On other hand, PAMAM-GA conjugate showed negligible cytotoxic response as compared to the free Gallic acid to the normal cells. In conclusion, findings of this study revealed that PAMAM-GA conjugate improves the bioavailability of GA and specificity towards cancer cellsto manifests apoptotic cell death. This indispensable approach may be beneficial for the revolution of anti-cancer therapy.

Communicated by Ramaswamy H. Sarma

Gallic acid (GA) is conjugated with 4.0 G PAMAM dendrimers via an amide linkage to form PAMAM-GA conjugate. The treatment of PAMAM-GA conjugate to cancer cells may induces loss of mitochondrial membrane potential with subsequent release of cytochrome c from mitochondrial intermembrane space into the cytosol where it forms apoptosome complex in association with Apaf-1 and Procaspase-9. This event leads to the proteolytic activation of caspase-3 and ultimately cells undergo toward apoptotic cell death.

Keywords:

• Cancer
• apoptosis
• gallic acid
• PAMAM dendrimers
• PAMAM-GA conjugate

Acknowledgements

FT-IR and NMR analysis were carried out at CSMCRI, Bhavanagar, Gujarat, India. Authors acknowledge IIAR, Puri Foundation for Education in India for providing junior Research Fellowship to KP, infrastructure facility and support. Department of Biotechnology, Gov of India is gratefully acknowledged for providing research grant to CP.

Authors contribution

Chandramani Pathak (CP): Conceptualization; Kavita Shirsath (KS), Khushbu Priyadarshi (KP), Bhargav Waghela (BW), Anupama Sharma (AS), Ajay Kumar (AK), Chandramani Pathak (CP): Methodology & Experimentation; CP, KS, KP, BW, AS: Data curation Software; KS, KP & CP: Writing and original draft preparation; KS, KP, BW & CP: Software and data validation; CP: Visualization, Investigation Supervision; CP: Writing- Reviewing and Editing.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was financially supported by the Department of Biotechnology, Ministry of Science & Technology, Government of India under Nano Science & Nanotechnology scheme (BT/PR14259/NNT/28/485/2010) to CP.