Exploring the Cytotoxic Effects of the Extracts and Bioactive Triterpenoids from Dillenia indica against Oral Squamous Cell Carcinoma: A Scientific Interpretation and Validation of Indigenous Knowledge

Abstract

Triterpenoids are ubiquitously distributed secondary metabolites, primarily scrutinized as a source of medication and preventive measures for various chronic diseases. The ease of isolation and excellent pharmacological properties of triterpenoids are notable reasons behind the exponential rise of extensive research on the bioactive triterpenoids over the past few decades. Herein, we attempted to explore the anticancer potential of the fruit extract of the ethnomedicinal plant Dillenia indica against oral squamous cell carcinoma (OSCC) and have exclusively attributed the efficacy of the extracts to the presence of two triterpenoids, namely, betulinic acid (BA) and koetjapic acid (KA). Preliminary in vitro screening of both BA and KA unveiled that the entities could impart cytotoxicity and induce apoptosis in OSCC cell lines, which were further well-supported by virtual screening based on ligand binding affinity and molecular dynamic simulations. Additionally, the aforementioned metabolites could significantly modulate the critical players such as Akt/mTOR, NF-κB, and JAK/STAT3 signaling pathways involved in the regulation of important hallmarks of cancer like cell survival, proliferation, invasion, angiogenesis, and metastasis. The present findings provide insight and immense scientific support and integrity to a piece of indigenous knowledge. However, in vivo validation is a requisite for moving to clinical trials and developing it as a commercial drug.

The health benefits of santol fruits and bioactive products isolated from Sandoricum koetjape Merr.: A scoping review

“…Molecular modeling suggested that KA can form stable complexes with these two proteins (Abubakar et al, 2019;Aswathy et al, 2021).…”

“…Molecular modeling suggested that KA can form stable complexes with these two proteins (Abubakar et al, 2019; Aswathy et al, 2021). Notably, KA would be able to stabilize mTOR via the formation of key H‐bonds between KA and several amino acids of mTOR including (a) the positively charged residues Lys1452 and Arg2217, (b) the polar residue Ser1584, (c) hydrophobic residue Tyr1587, as illustrated in Figure 6 (Aswathy et al, 2021). The postulated capacity of KA to target mTOR directly will necessitate an experimental validation, but the hypothesis is plausible and reminiscent of the situation reported with other pentacyclic triterpenoids such as betulinic acid and asiatic acid interacting with mTOR (Zulkipli et al, 2020; Guo et al, 2020).…”

Embelin: A novel XIAP inhibitor for the prevention and treatment of chronic diseases

“…[154,155] Lately, researchers are looking for natural products to target multiple signaling pathways and prevent the serious adverse side effects caused by the presently available mono-targeted therapies. [1,[156][157][158][159][160] Embelin has been shown to possess multiple anticancer properties in different types of malignancies. It targets multiple signaling pathways involved in the initiation, proliferation, and metastasis of various cancers.…”

The promising potential of piperlongumine as an emerging therapeutics for cancer

“…Since ancient times, plant-derived phytochemicals and herbal medicines are being explored as a treatment modality against different chronic diseases, including cancer, and thus have gained extensive popularity for possessing beneficial healing properties [23][24][25][26][27][28][29][30][31][32][33][34][35]. The healing properties of the plant-derived products are due to the presence of a wide range of biologically active alkaloids, flavonoids, tannins, diterpenoids, carotenoids, and phenolic compounds present in various parts [36][37][38][39][40][41][42]. Therefore, these compounds play a vital role in preventing cancer initiation and suppressing the process of cell proliferation, invasion, metastasis, and chemoresistance [43][44][45][46][47][48][49][50][51][52].…”