Abstract A19: Andrographolide analogue induces crosstalk between apoptosis and autophagy via inhibition of PI3K/Akt/mTOR pathway in human leukemic cells.

Current chemotherapeutic agents solely based on apoptosis induction have limited efficacy. Therefore, new therapeutic strategies and drugs still need to be explored. Various forms of programmed cell death are being increasingly implicated in anticancer therapy and the complex interplay among them is critical to the overall fate of cells. We elucidated the underlying mechanism of the most potent Andrographolide analogue (AG-4) mediated action that involved crosstalk between apoptosis and autophagy in human leukemic U937 cells. AG-4 induced cytotoxicity was associated with redox imbalance and apoptosis which involved mitochondrial depolarisation, altered apoptotic protein expressions, activation of the caspase cascade leading to cell cycle arrest. Incubation with caspase inhibitor Z-VAD-fmk or Bax siRNA decreased cytotoxic efficacy of AG-4 emphasising critical roles of caspase and Bax. In addition, AG-4 induced autophagy as evident from LC3-II accumulation, increased Atg protein expressions and autophagosome formation. Pre-treatment with 3-MA or Atg 5 siRNA suppressed the cytotoxic effect of AG-4 implying the pro-death role of autophagy. Furthermore, incubation with Z-VAD-fmk or Bax siRNA subdued AG-4 induced autophagy and pre-treatment with 3-MA or Atg 5 siRNA curbed AG-4 induced apoptosis - implying that apoptosis and autophagy act as partners in the context of AG-4 mediated action. AG-4 also inhibited PI3K/Akt/mTOR pathway. Inhibition of mTOR (by rapamycin or mTOR siRNA) or Akt (by LY294002 or Akt siRNA) augmented AG-4 induced apoptosis and autophagy signifying its role in apoptosis-autophagy crosstalk. Thus, these findings provide new perspective of AG-4 as potential molecule targeting programmed cell death for future cancer therapeutics.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A19.

Citation Format: Deepak Kumar, Rajneeta Roy, Chinmay Chowdhury, Mitali Chatterjee, Padma Das. Andrographolide analogue induces crosstalk between apoptosis and autophagy via inhibition of PI3K/Akt/mTOR pathway in human leukemic cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A19.