The process of cell growth regulation during the cell cycle involves the coordination of specific cyclins with their corresponding cyclin-dependent kinases (CDKs) to form functional complexes, which operate at distinct checkpoints (Lim and Kaldis, 2013). These complexes enable cells to transition from one phase of the cell cycle to the next. This regulatory mechanism ensures proper cell growth and division and helps to prevent errors from occurring. Ultimately, the cell cycle progresses until it is ready to enter a new phase (Lu et al., 2006). Cell cycle progression is controlled by the activity of CDKs, which are negatively regulated by specific CDK inhibitors. When the regulation of these cell cycle checkpoints fails, it can lead to genomic instability, DNA damage, and mutations, ultimately resulting in genetic disturbances and potentially giving rise to cancer (Yang et al., 2010). It is critical for the cell cycle to be carefully controlled and for the checkpoints to function properly to maintain the integrity of the genetic material and prevent the development of cancer (Yang et al., 2010).

AA, a compound derived from Pinus palustris, showed promising anti-proliferative activity against the human breast cancer cell line MCF-7 through causing G2/M cell arrest and subG0 -G1 phase cell cycle arrest. The AA caused cell cycle arrest and induction of apoptosis in MCF-7 cells (Haffez et al., 2022). AA impacted the cell cycle distribution of NSCLC, PC-9 and H1975 cells by arresting them at the G0/G1 phase. The expression of cell cycle-related proteins, such as cyclin D1 and cdk4, was also downregulated by AA, suggesting that it effectively arrested the cells in the G0/G1 phase through reducing the expression of these proteins (Liu et al., 2019). The summarized form of AA induced cells cycle arrest is depicted in Figure 1A and Table 1.

In induction of apoptosis, the mitochondrial dependent pathway plays a crucial role, and its disruption can prevent apoptosis from occurring. The Bcl-2 family proteins regulate this pathway by modulating the mitochondrial membrane permeability, which determines the release of different apoptotic proteins from mitochondria like cytochrome c (Cyt-c) (Wu and Bratton, 2013). BclxL and Bcl-2 are the anti-apoptotic proteins which promote cell survival by preventing apoptosis, while pro-apoptotic proteins such as BAX induce apoptosis by creating mitochondrial stress (Reed, 2006). Plant-derived compounds are viewed as a safe and cost-effective approach to targeting cancer through various pathways, including the mitochondrial-dependent pathway. These compounds act through multiple mechanisms including mitochondrial dependent pathway, to induce apoptosis in cancer cells, making them a promising therapeutic option (Ahmad et al., 2019b; Ahmad and Gamallat, 2021).

In breast cancer MCF-7 and NSCLC cells, AA downregulated Bcl-2 and upregulated Bax, resulting in the release of Cyt-c from mitochondria and increasing the expression of cleaved PARP, which ultimately led to apoptosis (Liu et al., 2019; Haffez et al., 2022). The AA mechanisms are further summarized in Figure 1B and Table 1.

Proteins from the Tumor Necrosis Factor (TNF) family, including Fas or TNF-receptor-1 (TNFR-1), activate the extrinsic apoptosis pathway. This pathway is an important mechanism for inducing programmed cell death (Locksley et al., 2001). TNFR-1 or Fas proteins through Fas associated death domains activate the caspase-8, which further activate the caspase-3 and help in cells apoptosis (Ashkenazi, 2008; Fulda, 2015). Natural products regulate this pathway in different cancers (Fatehchand et al., 2017; Kang et al., 2017). AA is a natural product derived from medicinal plants.

The AA regulate the EAP through overexpression of apoptotic genes Fas, Fasl which further increase the expression of caspase-8, caspase-8 results in activation of caspase-3 and led the cells to apoptosis (Haffez et al., 2022). These mechanisms of AA are further summarized in Figure 1B and Table 1.

Protein kinase C (PKC) has been traditionally viewed as an oncoprotein, meaning that it was believed help in progression of cancer cells growth and development (Newton, 2018). PRKAA1, is the subunit of AMP activated protein kinases (AMPK), which play an important role in control of cellular metabolism through its phosphorylation. Recent studies have found that genetic variations in PRKAA1 have a close link with gastric cancer. These findings suggest that PRKAA1 and AMPK may play a significant role in gastric cancer progression and development (Zhang et al., 2020) which make it an important therapeutic target in cancer treatment.

AA has been shown to downregulate PKC-a levels while overexpressing PRKAA1, a key kinase in MCF-7 resistance and metastasis cells. This overexpression activates AMPK (Haffez et al., 2022) as shown in Figure 1B and Table 1.

PI3K/AKT/mTOR pathway plays an important role in regulating cell proliferation, protein synthesis, and apoptosis. Inhibition of this pathway has been shown to have therapeutic potential for various diseases, including cancer (Courtney et al., 2010; Steelman et al., 2011). Understanding the specific mechanisms of activation of this pathway in different types of cancer is important for developing targeted therapies that can inhibit its activity and suppress tumor growth (Samuels et al., 2004; Samuels and Velculescu, 2004; Wong et al., 2010). Plant-derived compounds are a promising approach to treating cancer, as they are generally considered safe and cost-effective. These compounds have been shown to target cancer cells through different pathways, including the PI3K/AKT and ERK pathways, which play crucial roles in regulating cell growth and survival. By targeting these pathways, plant-derived compounds have the potential to inhibit the growth and proliferation of cancer cells, making them a promising avenue for the development of novel cancer therapies (Ahmad and Gamallat, 2021). AA is also a natural product derive from plant.

AA caused a gradual decrease in PI3K protein levels and significantly inhibited Akt activation in a dose-dependent manner. There was no significant influence on phosphorylated p38 or phosphorylated ERK1/2 (Hsieh et al., 2015). These mechanisms of AA are depicted in Figure 1B and Table 1.

The NF-kB is a complex pathway which is consist of five homo and hetero-dimers of Reticuclo-endotheliosis oncogenes cellular (Rel) family including c-Rel, RelA(p65), NF-kB1 (p50/p65), RelB and NF-kB2 (p50/p65) (Sen and Baltimore, 1986). In different cancers the NF-kB pathway become dysregulated (Perkins, 2007) including colon, breast, liver, ovarian, leukemia and lymphoma cancers (Bassères and Baldwin, 2006; Prasad et al., 2010; Arkan and Greten, 2011). As dysregulation of NF-kB pathway is involved in the progression of different cancers, therefore it is a good therapeutic target in treatment of different cancers. Numerous natural substances have been identified as regulators of the NF-kB pathway in various types of cancer (Ahmad et al., 2021; Ahmad and Gamallat, 2021).

In NSCLC, AA downregulates the TNF-α induced activation of IKKβ, IkB and block the NF-kB nuclear translocation dose-dependently. AA directly bound to IKKβ, while its binding with IKKα was much lower, suggesting specificity for IKKβ. The causal relationship between the functional effects and the signaling pathway was supported by the results of overexpression of IKKβ in PC-9 cells, which showed impaired anti-proliferative and apoptosis effects of AA. The authors have also confirmed the binding of AA to IKKβ by surface plasmon resonance (SPR) experiments and the specificity of binding was shown to be higher for IKKβ than IKKα. The study concludes that AA could be a promising lead compound for the discovery of novel IKKβ inhibitors and a potential agent for the treatment of NSCLC (Liu et al., 2019). In addition, AA downregulate the proliferation (VEGF, IGFR1, TGF-β) and oncogenic genes (C-myc and NF-κB), and increased levels of antioxidants (total antioxidant capacity as compared to negative control without (W/O) H₂O₂) (Haffez et al., 2022). These mechanisms of AA are further summarized in Figure 1C and Table 1.

Ferroptosis is a type of cell death that relies on intracellular iron and differs from other forms of cell death such as apoptosis, necrosis, and autophagy (Zhang et al., 2022). Research suggests that ferroptosis can play a significant role in suppressing tumor growth, which presents an opportunity for cancer therapy (Zhang et al., 2022). However, developing resistance to cancer therapy remains a challenge, and efforts to overcome drug resistance have been the focus of numerous preclinical and clinical studies (Zhang et al., 2022). Interestingly, ferroptosis has been associated with resistance to cancer therapy, and triggering ferroptosis has been shown to reverse drug resistance (Zhang et al., 2022).

AA has a selective effect on inhibiting the viability of bladder cancer (BC) cell lines (J82, T-24, 5637) in a time and dose dependent manner (Xu et al., 2023). It has little effect on the normal urothelial cell line SV-HUC-1 (Xu et al., 2023). Gene expression analysis shows that the ferroptosis pathway and redox signaling pathway are enriched after AA treatment, suggesting AA has selectively antitumor effects against BC (Xu et al., 2023) The type of cell death caused by AA in bladder cancer cells was investigated using various inhibitors (Xu et al., 2023). The apoptosis (z.VAD-FMK, z. VAD) and necrosis inhibitors (Necrostatin-1, Nec) had little effect on the viability of BC cells, while ferroptosis inhibitors and ROS scavengers (N-Acetyl-L-cysteine, NAC) significantly increased it. Cell death assays showed that only ferroptosis inhibitors (Ferrostatin-1, Fer-1; Liproxstatin-1, Lip-1; Deferoxamine, DFO) protected BC cells from AA-induced death. These findings suggest that AA may induce ferroptosis in BC cells (Xu et al., 2023).

The mechanism of action between AA and IKKβ was shown to be through hydrophobic interactions by molecular docking and molecular dynamics (MD) simulations (Liu et al., 2019). AA has strong binding efficiency with the AchE and HDAC3 receptors, as indicated by Ligplot analysis and root mean square deviation analysis. In vitro tests with HeLa cells showed that abietic acid induces apoptosis in a concentration-dependent manner, suggesting its potential as a promising terpenoid for treating Alzheimer’s disease and cervical cancer (Ramnath et al., 2018).