The .BETA.-Carboline Alkaloid Harmol Induces Cell Death via Autophagy but Not Apoptosis in Human Non-small Cell Lung Cancer A549 Cells

Abstract

Lung cancer is a leading cause of death worldwide, and the long-term survival rate of lung cancer patients is one of the lowest among cancers.1,2) Two major types of lung cancer have been identified: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC, the most prevalent subtype, is relatively resistant to chemotherapy and radiation therapy. On the other hand, SCLC is initially highly sensitive to chemotherapy and radiation therapy, but shows resistance to treatment in the majority of patients.3) The high mortality in NSCLC is due to the difficulty of early diagnosis and its high potential for local invasion and distant metastasis. Although relatively effective chemotherapeutic agents have been developed, lung cancer still has a low cure rate. Furthermore, the adverse effects of chemotherapeutic compounds often hamper the quality of life of lung cancer patients. Therefore, the discovery of effective novel prophylactic, diagnostic, and therapeutic treatments for NSCLC is urgently needed."Apoptosis" has been used as a synonym for programmed cell death (PCD), and is a well-known form of PCD. Since the 1960s, various morphological forms of PCD have been recognized. Clarke classified cell death into 4 types, including type I PCD (apoptosis) and type II PCD (autophagy). 4)Numerous studies have demonstrated that most chemotherapy agents and certain naturally occurring compounds induce cell death by activating the apoptotic pathway. It is thought that apoptosis induction in tumor cells with either drugs or natural products is effective therapy for cancer and immune system diseases. On the other hand, autophagy is one of the major regulatory mechanisms in the degradation of intracellular proteins and organelles. 5,6) During autophagy, the cytosol and whole organelles become encased in double-membrane vacuoles such as autophagosomes, and subsequently fuse with lysosomes.5) Degradation of the sequestered material generates nucleotides, amino acids, and free fatty acids that are recycled for macromolecular synthesis and ATP generation.7) Although originally characterized as a survival response to nutrient deficiency, autophagy is now recognized as frequently induced in response to a variety of stressors to maintain cellular homeostasis. [8][9][10][11][12] In recent years, the importance of autophagy has been emphasized in various biological fields, including cancer. 9,[13][14][15] Furthermore, cancer cells show less autophagy than normal cells. 16,17) These findings indicate that autophagy induction is an attractive modality of anticancer therapy.b-Carboline alkaloids occur in a number of medicinal plants such as Peganum harmala, Passiflora edulis, Passiflora incarnata, and Banisteriopsis caapi.18,19) These plants have been used in traditional medicine to treat asthma, jaundice, lumbago, and other human ailments.19-21) Recently, it has been reported that certain b-carboline alkaloids and their related compounds have cytotoxic effects on cancer cells. [22][23][24] We also reported previously that harm...

Peneciraistin C induces caspase‐independent autophagic cell death through mitochondrial‐derived reactive oxygen species production in lung cancer cells

“…In addition, the side-effects of chemotherapeutic drugs often hamper the quality of life of lung cancer patients. (4) Therefore, the discovery of effective novel molecular targeted therapies for lung cancer is urgently needed.…”

Fenugreek extract as an inducer of cellular death via autophagy in human T lymphoma Jurkat cells

“…LC3 plays a critical role in autophagy and is considered suitable marker of this process [44]. In the present study, fenugreek extract increased LC3 transcript level with increasing concentrations of fenugreek extract over a period of 48 h. Harmol, a beta carotenoid, induced death of lung cancer cells A549 was associated with increased expression of LC3 [45] and siRNA knockdown of LC3 resulted in blockade of cell death, which, in turn, served to prove that harmol-induced autophagy was only a death mechanism [45]. Transcripts of beclin 1 and ATG5, the other autophagic pathway genes, did not show any decline in our fenugreek-treated Jurkat cells and this was similar to harmol-treated A549 cells which failed to show any changes in the expression and phosphorylation of beclin 1 [45].…”

Influence of β-Carboline Produced from Glucose and Tryptophan on Protein Synthesis of Chicken Embryo Myoblasts

“…This result implied that the elevation of PHP-THβC concentration within the physiological range could reduce muscle protein synthesis. It was reported that harmol, a β-carboline alkaloid, induced autophagy and cell death in human lung cancer cells via activation of the ERK1/2 pathway but not of the Akt/ mTOR pathway (Abe et al, 2011). Although the decrease in muscle protein synthesis by PHP-THβC may relate to the activation of the ERK1/2 pathway, this issue would be elucidated in the future.…”