Curcumin diethyl disuccinate, a prodrug of curcumin, enhances anti-proliferative effect of curcumin against HepG2 cells via apoptosis induction

Chawanphat Muangnoi, Pahweenvaj Ratnatilaka Na Bhuket, Ponsiree Jithavech, Wiwat Supasena, Luminita Paraoan, Suthiluk Patumraj, Pornchai Rojsitthisak

Research output: Contribution to journalArticle (journal)peer-review

21 Citations (Scopus)

Abstract

Curcumin (Cur) has been reported to have anti-hepatocellular carcinoma activity but its poor oral bioavailability limits its further development as a chemotherapeutic agent. We synthesized previously a succinate ester prodrug of Cur, curcumin diethyl disuccinate (CurDD) with better chemical stability in a buffer solution pH 7.4. Here, we further investigated and compared the cellular transport and anti-proliferative activity against HepG2 cells of CurDD and Cur. Transport of CurDD across the Caco-2 monolayers provided a significantly higher amount of the bioavailable fraction (BF) of Cur with better cytotoxicity against HepG2 cells compared to that of Cur (p < 0.05). Flow cytometric analysis showed that the BF of CurDD shifted the cell fate to early and late apoptosis to a higher extent than that of Cur. The Western blot analysis revealed that CurDD increased Bax protein expression, downregulated Bcl-2 protein, activated caspase-3 and -9 and increased LC3-II protein level in HepG2 cells. Flow cytometric and immunoblotting results suggest that CurDD can induce HepG2 cell death via an apoptotic pathway. We suggest that CurDD can overcome the limitations of Cur in terms of cellular transport with a potential for further extensive in vitro and in vivo studies of anti-hepatocellular carcinoma effects.

Original languageEnglish
Pages (from-to)11718
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 12 Aug 2019
Externally publishedYes

Keywords

  • Antineoplastic Agents, Phytogenic/chemistry
  • Apoptosis/drug effects
  • Biological Transport
  • Caco-2 Cells
  • Caspase 3/genetics
  • Caspase 9/genetics
  • Cell Survival/drug effects
  • Curcumin/analogs & derivatives
  • Gene Expression Regulation, Neoplastic
  • Hep G2 Cells
  • Humans
  • Microtubule-Associated Proteins/genetics
  • Prodrugs/chemistry
  • Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
  • Signal Transduction
  • Succinates/chemistry
  • bcl-2-Associated X Protein/agonists

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