Andrographolide causes apoptosis via inactivation of STAT3 and Akt and potentiates antitumor activity of gemcitabine in pancreatic cancer

Toxicol Lett. 2013 Sep 12;222(1):23-35. doi: 10.1016/j.toxlet.2013.06.241. Epub 2013 Jul 8.

Abstract

Gemcitabine is a first-line drug utilised in the chemotherapy of pancreatic cancer; however, this drug induces chemo-resistance and toxicity to normal tissue during treatment. Here, we firstly report that andrographolide (ANDRO) alone not only has anti-pancreatic cancer activity, but it also potentiates the anti-tumour activity of gemcitabine. Treatment with ANDRO alone inhibits proliferation of the pancreatic cancer cell lines in a dose- and time-dependent manner in vitro. Interestingly, ANDRO induces cell cycle arrest and apoptosis of pancreatic cancer cells by inhibiting STAT3 and Akt activation, upregulating the expression of p21(WAF1) and Bax, and downregulating the expression of cyclinD1, cyclinE, survivin, X-IAP and Bcl-2. Additionally, ANDRO combined with gemcitabine significantly induce stronger cell cycle arrest and more obvious apoptosis than each single treatment. The mechanistic study demonstrates that this synergistic effect is also dependent on the inhibition of STAT3 and Akt activations which subsequently regulates the pathways involved in the apoptosis and cell cycle arrest. Furthermore, both ANDRO alone and the combination treatments exhibit efficacious anti-tumour activity in vivo. Overall, our results provide solid evidence supporting that ANDRO alone or its combination with gemcitabine is a potential chemotherapeutic approach for treating human pancreatic cancer in clinical practice.

Keywords: Akt; Andrographolide; Gemcitabine; Pancreatic cancer; STAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Count
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Coloring Agents
  • Cytochromes c / metabolism
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Diterpenes / pharmacology*
  • Drug Synergism
  • Flow Cytometry
  • Gentian Violet
  • Humans
  • Ki-67 Antigen
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Pancreatic Neoplasms / drug therapy*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antimetabolites, Antineoplastic
  • Coloring Agents
  • Diterpenes
  • Ki-67 Antigen
  • STAT3 Transcription Factor
  • Deoxycytidine
  • andrographolide
  • Cytochromes c
  • gemcitabine
  • Proto-Oncogene Proteins c-akt
  • Gentian Violet