Antitumor Effects of Ononin by Modulation of Apoptosis in Non-Small-Cell Lung Cancer through Inhibiting PI3K/Akt/mTOR Pathway

Abstract

Lung cancer is a leading global cause of cancer-related death in both males and females. Non-small-cell lung cancer (NSCLC) is the most commonly diagnosed cancer type that can be difficult to control with conventional chemotherapeutic and surgical approaches resulting in a poor prognosis. Paclitaxel (PTX) is a commonly used chemotherapeutic drug for NSCLC, which can cause tissue injury in healthy cells and affect the quality of life in patients with cancer. In order to treat NSCLC, alternative medications with minimal or no side effects are highly needed. Ononin is an isoflavone glycoside extracted from Astragali Radix (AR) that has various pharmacological activities. Therefore, this study investigated whether ononin inhibits NSCLC progression and promotes apoptosis synergistically with PTX both in vitro and in vivo. Antitumorigenic properties of ononin were determined by MTT assay, colony formation assay, migratory capacity, and apoptotic marker expression in A549 and HCC827 cells. The combination of ononin with PTX increased the expression of apoptotic markers and ROS generation and inhibited cell proliferation through the PI3K/Akt/mTOR signaling pathways. Furthermore, ononin prevented the translocation of NF-κB from cytosol to the nucleus. Also, we used the xenograft NSCLC mice model to confirm the in vivo antitumorigenic efficacies of ononin by reduction of CD34 and Ki67 expressions. Based on the histological analysis, the cotreatment of PTX and ononin reduced PTX-induced liver and kidney damage. Overall, our findings suggested that the therapeutic index of PTX-based chemotherapy could be improved by reducing toxicity with increasing antitumor capabilities when combined with ononin.

Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells

“…In recent years, more and more research studies have been conducted on the relationship between ROS and cancer. ROS is considered to be an important anticancer target due to the different roles of different levels of ROS in various stages of cancer development, and many studies have shown that therapeutic strategies targeting ROS are significantly effective in the treatment of various diseases, including human lung cancer, colorectal cancer, breast cancer, and glioblastoma [ 61 , 132 , 133 , 134 ]. Therefore, based on the effectiveness of excessive ROS for cancer treatment, new anticancer therapies targeting ROS generation can be regarded as a good solution to the current problems of cancer drug resistance and the low efficacy of traditional anticancer therapies.…”

Ononin: A comprehensive review of anticancer potential of natural isoflavone glycoside

“…The results showed that a dose‐dependent manner treatment with ononin synergistically with or without PTX significantly inhibited the proliferation of A549 and HCC827 cells. [ 3 ] Furthermore, cotreatment of ononin with PTX significantly increased the rate of cell death and ROS generation and decreased MMPs in human lung cancer A549 and HCC827 cells. [ 3 ] The production of ROS can also promote anti‐tumorigenic effects, initiating oxidative stress‐induced tumor cell death.…”

“…[2] It has demonstrated anti-inflammatory, antiproliferative, proapoptotic, antiangiogenic, and antimetastatic effects across diverse cancer models, including lung, laryngeal, colon, breast, and osteosarcoma. [1,[3][4][5][6] Ononin targets multiple molecular pathways, hindering malignant development and tumor growth. [3] This review compiles and systematically presents current knowledge about ononin's anticancer potential.…”

“…[1,[3][4][5][6] Ononin targets multiple molecular pathways, hindering malignant development and tumor growth. [3] This review compiles and systematically presents current knowledge about ononin's anticancer potential. It also explores how this phytochemical affects the resistance mechanisms of conventional chemotherapy drugs.…”

Anti-Invasive and Anti-Migratory Effects of Ononin on Human Osteosarcoma Cells by Limiting the MMP2/9 and EGFR-Erk1/2 Pathway

“…It has a wide range of biological effects, such as antioxidant, antidiabetic, anti-obesity, neuroprotective, cardioprotective, antiviral, and anti-inflammatory qualities [11][12][13][14][15][16]. Ononin exhibits dose-and time-dependent manners of anti-cancer effects, including the larynx [17], colon [18], lung [19], and breast [20]. In addition, ononin inhibited ER stress and apoptosis, likely activating the SIRT3 pathway, and protected against doxorubicin-induced cardiotoxicity [21].…”