Sesquiterpenoid-rich Java Ginger rhizome extract prompts autophagic cell death in cervical cancer cell SiHa mainly by modulating cellular redox homeostasis

Java Ginger or Curcuma zanthorrhiza Roxb. has long gained focus among tribal people of Java, for its medicinal properties mainly against gynaecological challenges. The present study aims to identify the most potent phytocompound present in the extract and determine primary mode of action accountable for cytotoxic activity of Curcuma zanthorrhiza rhizome extract against HPV16-positive SiHa cervical cancer cells. The phytochemically-rich extract of rhizome (CZM) was capable to inhibit proliferation of target cells in a dose-dependent manner with an IC50 of 150 mu g/ml. Dysregulation of intercellular antioxidant defence system resulted to surges in ROS and RNS level, increased calcium concentration and compromised mitochondrial membrane potential. Nucleus got affected, cell cycle dynamics got impaired while clonogenicity and migration ability diminished. Expression of viral oncogenes E7 and E6 decreased significantly. Accumulation of toxic cell metabolite and decrease in level of essential ones continued. Finally, alteration in PI3K/AKT/mTOR signalling route was followed by onset of autophagic cell death concomitant with the upregulated expression of Beclin1, Atg5-12 and LC3II. Curcumin and a novel crystal as well as few phyto-fractions were isolated by column chromatography. Of these, curcumin was found to be most potent in inducing cytotoxicity in SiHa while two other fractions also showed significant activity. Thus, CZM acted against SiHa cells by inducing autophagy that commences in compliance to the changes in PI3K/AKT/mTOR pathway mainly in response to oxidative stress. To the best of our knowledge this is the first report of Curcuma zanthorrhiza Roxb. inducing autophagy.

Automated summary

This study aims to identify the most potent phytocompound present in the extract of Curcuma zanthorrhiza rhizome and determine its primary mode of action against HPV16-positive SiHa cervical cancer cells. The extract was found to inhibit cell proliferation in a dose-dependent manner and induce cytotoxicity through dysregulation of antioxidant defense system and activation of the PI3K/AKT/mTOR pathway, leading to autophagic cell death. This is the first report of Curcuma zanthorrhiza Roxb. inducing autophagy.