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journal homepage: www.elsevier.com/locate/canlet
Cannabidiol-induced apoptosis is mediated by activation of Noxa in human T colorectal cancer 916210-98-5
Soyeon Jeonga,1, Hye Kyeong Yunb,1, Yoon A Jeongb, Min Jee Job, Sang Hee Kangc, Jung Lim Kima, Dae Yeong Kimb, Seong Hye Parkb, Bo Ram Kima, Yoo Jin Nab, Sun Il Leec, Han Do Kimd, Dae Hyun Kimd, Sang Cheul Oha,b,∗∗, Dae-Hee Leea,b,∗ a Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, South Korea
b Graduate School of Medicine, College of Medicine, Korea University, Seoul, 08308, Republic of Korea
c Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
Bcl-2 protein family
Apoptotic cell death
Cannabidiol (CBD), one of the compounds present in the marijuana plant, has anti-tumor properties, but its mechanism is not well known. This study aimed to evaluate the apoptotic action of CBD in colorectal cancer (CRC) cells, and focused on its eﬀects on the novel pro-apoptotic Noxa-reactive oxygen species (ROS) signaling pathway. CBD experiments were performed using the CRC cell lines HCT116 and DLD-1. CBD induced apoptosis by regulating many pro- and anti-apoptotic proteins, of which Noxa showed significantly higher expression. To understand the relationship between Noxa and CBD-induced apoptosis, Noxa levels were downregulated using siRNA, and the expression of apoptosis markers decreased. After ROS production was blocked, the level of Noxa also decreased, suggesting that ROS is involved in the regulation of Noxa, which along with ROS is a well-known pro-apoptotic signaling agents. As a result, CBD induced apoptosis in a Noxa-and-ROS-dependent manner. Taken together, the results obtained in this study re-demonstrated the eﬀects of CBD treatment in vivo, thus confirming its role as a novel, reliable anticancer drug.
Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide . Although the development in chemotherapy for CRC has increased overall survival, side eﬀects such as cytotoxicity and resistance continue to limit its utilization. Therefore, there is an urgent need to develop more eﬀective agents for CRC patients.
Noxa is a pro-apoptotic member belonging to the Bcl-2 protein fa-mily that is unique in that it contains only Bcl-2 homology 3 domain . During apoptosis, activated Noxa is translocated to the mi-tochondria, inducing cytochrome c release and subsequent caspase-9 activation . Noxa induces Bax-mediated mitochondrial dysfunction via indirect inhibition of the anti-apoptotic Bcl-2 protein family mem-bers . Because Noxa plays a key role in apoptotic cell death, it serves as excellent intracellular target that is an eﬀective therapeutic
target for cancer [4,11]. Noxa is activated by various factors such as ultraviolet radiation, etoposide, hypoxia, mitogenic stimulation, and reactive oxygen species (ROS).
ROS, including O2− (superoxide radical), ●OH (hydroxyl radical), and H2O2 (hydrogen peroxide), play a major role in numerous cellular events . In mammalian cells, the mitochondrial electron transport chain is the primary sites of ROS generation . Excessive ROS can induce mitochondrial dysfunction by decreasing the mitochondrial membrane potential and causing electron leakage, leading to apoptosis [3,6,12].
Cannabidiol (CBD) is one of the best known cannabinoid family, which includes the members of the Cannabis sativa family . Can-nabinoids interact with specific Gαi protein-coupled receptors, CB1 (Central receptor) and CB2 (Peripheral receptor) . However, CBD does not bind well to CB1 and CB2 receptors, and the mechanism
∗ Corresponding author. Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University Medical Center, Korea University, Seoul, 08308, Republic of Korea. ∗∗ Corresponding author. Division of Oncology/Hematology, Department of Internal Medicine, Korea University Guro Hospital, 148, Gurodong-gil, Guro-gu, Seoul, 08308, South Korea.