Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide and remains the most prevalent. Interplay between PI3K/AMPK/AKT and MAPK pathways is a crucial effector in lung cancer growth and progression. These signals transduction protein kinases serve as good therapeutic targets for non-small cell lung cancer (NSCLC) which comprises up to 90% of lung cancers. Here, we described whether 21α-Methylmelianodiol (21α-MMD), an active triterpenoid derivative of Poncirus trifoliate, can display anticancer properties by regulating these signals and modulate the occurrence of multidrug resistance in NSCLC cells. We found that 21α-MMD inhibited the growth and colony formation of lung cancer cells without affecting the normal lung cell phenotype. 21α-MMD also abrogated the metastatic activity of lung cancer cells through the inhibition of cell migration and invasion, and induced G0/G1 cell cycle arrest with increased intracellular ROS generation and loss of mitochondrial membrane integrity. 21α-MMD regulated the expressions of PI3K/AKT/AMPK and MAPK signaling which drove us to further evaluate its activity on multidrug resistance (MDR) in lung cancer cells by specifying on P-glycoprotein (P-gp)/MDR1-association. Employing the established paclitaxel-resistant A549 cells (A549-PacR), we further found that 21α-MMD induced a MDR reversal activity through the inhibition of P-gp/MDR1 expressions, function, and transcription with regained paclitaxel sensitivity which might dependently correlate to the regulation of PI3K/mTOR signaling pathway. Taken together, these findings demonstrate, for the first time, the mechanistic evaluation in vitro of 21α-MMD displaying growth-inhibiting potential with influence on MDR reversal in human lung cancer cells.
Highlights
Lung cancer is the most common cancer worldwide for decades, and it accounts for approximately 1.38 million deaths each year for both men and women in the United States alone
This was as consequence of its possible anti-oxidative function, which may require cofactors such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1 β) as 21α-MMD was shown to attenuate their mRNA expressions in macrophages [47]
Curious to know whether 21αMMD can exert anti-oxidative function or in other way support the redox activity against non-small cell lung cancer (NSCLC) cells, we examined its activity on ROS-triggered regulatory utility by which 21α-MMD significantly increased intracellular ROS generation which might be related to Akt signal since an enhanced inhibition was observed after lung cancer cells were treated with relative low-concentration of 21α-MMD and N-acetyl cysteine, a radical scavenger
Summary
Lung cancer is the most common cancer worldwide for decades, and it accounts for approximately 1.38 million deaths each year for both men and women in the United States alone. The prognosis associated with the disease is very poor delaying the diagnosis until late advanced stages and treatment options are limited, resulting in almost 90% death rate due to treatment failure caused by undetected metastasis progression [1]. The mechanism by which most natural products exhibit their therapeutic potential is less well understood. Triterpenoids have been taking an increasing attention lately in lung cancer therapeutics because of their reported chemopreventive and therapeutic potential both in vitro and in vivo [3,4]. 21α-Methylmelianodiol (21α-MMD) is a natural triterpenoid and an isomer of 21-methylmelianodiols first isolated from the fruits of Poncirus trifoliata (Rutaceae), which has long been used in Oriental medicine as a remedy for allergic inflammation. There has been no report further evaluating its anticancer potential and mechanism of action in lung cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
