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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 PLoS+One
2015 ; 10
(10
): e0139657
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Andrographolide Analogue Induces Apoptosis and Autophagy Mediated Cell Death in
U937 Cells by Inhibition of PI3K/Akt/mTOR Pathway
#MMPMID26436418
Kumar D
; Das B
; Sen R
; Kundu P
; Manna A
; Sarkar A
; Chowdhury C
; Chatterjee M
; Das P
PLoS One
2015[]; 10
(10
): e0139657
PMID26436418
show ga
BACKGROUND: Current chemotherapeutic agents based on apoptosis induction are
lacking in desired efficacy. Therefore, there is continuous effort to bring about
new dimension in control and gradual eradication of cancer by means of ever
evolving therapeutic strategies. Various forms of PCD are being increasingly
implicated in anti-cancer therapy and the complex interplay among them is vital
for the ultimate fate of proliferating cells. We elaborated and illustrated the
underlying mechanism of the most potent Andrographolide analogue (AG-4) mediated
action that involved the induction of dual modes of cell death-apoptosis and
autophagy in human leukemic U937 cells. PRINCIPAL FINDINGS: 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 acted as partners in the context of AG-4 mediated action. AG-4 also
inhibited PI3K/Akt/mTOR pathway. Inhibition of mTOR or Akt augmented AG-4 induced
apoptosis and autophagy signifying its crucial role in its mechanism of action.
CONCLUSIONS: Thus, these findings prove the dual ability of AG-4 to induce
apoptosis and autophagy which provide a new perspective to it as a potential
molecule targeting PCD for future cancer therapeutics.