The β-carboline alkaloid harmol induces cell death via autophagy but not apoptosis in human non-small cell lung cancer A549 cells

Akihisa Abe, Hiroyuki Yamada, Shota Moriya, Keisuke Miyazawa
Biological & Pharmaceutical Bulletin 2011, 34 (8): 1264-72
β-Carboline alkaloids are naturally occurring plant substances that have a wide spectrum of neuropharmacological, psychopharmacological, and antitumor effects. Recently, we have demonstrated that harmol, a β-carboline alkaloid, induces apoptosis by caspase-8 activation independently from Fas/Fas ligand interaction in human non-small cell lung cancer (NSCLC) H596 cells. Here, we found that harmol induces autophagy and cell death in human NSCLC A549 cells. Although harmol induced cell death in A549 cells in a significant dose- and time-dependent manner, it did not induce caspase-3, caspase-8, or caspase-9 activity. Furthermore, cleavage of poly-(ADP-ribose)-polymerase was not induced in A549 cells by harmol treatment. Autophagy, but not apoptosis, was detected by electron microscopy in A549 cells treated with 70 µM harmol. Pretreatment of A549 cells with 3-methyladenine, an autophagy inhibitor, as well as small interfering RNA (siRNA)-mediated knockdown of LC3, both suppressed harmol-induced cell death. These suggest that the induction of autophagy by harmol precedes cell death. The cytotoxicity of some anticancer agents is reportedly linked to autophagy induction. The 2 major autophagy regulatory pathways are the Akt/mammalian target of rapamycin (mTOR) pathway and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Although harmol treatment showed no effect on the Akt/mTOR pathway, it transiently activated the ERK1/2 pathway. However, inhibition of the ERK1/2 pathway using the mitogen-activated protein kinase (MEK)/ERK inhibitor U0126 partially suppressed autophagy. Therefore, although activation of the ERK1/2 pathway might be related to harmol-induced autophagy, another major pathway may also be involved in A549 cells.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"