Curcumin and Plumbagin Synergistically Target the PI3K/Akt/mTOR Pathway: A Prospective Role in Cancer Treatment

Abstract

Cancer development is associated with the deregulation of various cell signaling pathways brought on by certain genetic and epigenetic alterations. Therefore, novel therapeutic strategies have been developed to target those pathways. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) pathway is one major deregulated pathway in various types of cancer. Several anticancer drug candidates are currently being investigated in preclinical and/or clinical studies to target this pathway. Natural bioactive compounds provide an excellent source for anticancer drug development. Curcumin and plumbagin are two potential anticancer compounds that have been shown to target the PI3K/Akt/mTOR pathway individually. However, their combinatorial effect on cancer cells is still unknown. This study aims to investigate the synergistic effect of these two compounds on the PI3K/Akt/mTOR pathway by employing a sequential molecular docking and molecular dynamics (MD) analysis. An increase in binding affinity and a decrease in inhibition constant have been observed when curcumin and plumbagin were subjected to sequential docking against the key proteins PI3K, Akt, and mTOR. The MD simulations and molecular mechanics combined with generalized Born surface area (MM-GBSA) analyses validated the target proteins’ more stable conformation when interacting with the curcumin and plumbagin combination. This indicates the synergistic role of curcumin and plumbagin against cancer cells and the possible dose advantage when used in combination. The findings of this study pave the way for further investigation of their combinatorial effect on cancer cells in vitro and in vivo models.

Curcumin, its derivatives, and their nanoformulations: Revolutionizing cancer treatment

“…Cancer is the second most fatal disease and a major global public health concern 1 . If the current trend continues, it could become the leading cause of mortality in most countries 2 . As per the latest report, the United States of America is expected to experience 1,958,310 new cancer cases and 609,820 cancer deaths in 2023, only 3 .…”

Evaluation of the Antiproliferative Potential of Yellow Jaboticaba (Myrciaria glazioviana) Extracts Against Human Cervical Cancer (HeLa cells line) and the Analysis of Their Chemical Composition by HPLC‐HRESIMS

“…[4] Some compounds of natural origin are targets of research and show promising results, such as curcumin, plumbagin and flavopiridol, which are capable of blocking the PI3K/Akt/mTOR pathway, which appears deregulated in different types of cancer. [4,5] Furthermore, there are chemotherapy drugs derived from natural products used in the clinic, such as the alkaloids vinblastine and vincristine, extracted from the species Catharanthus roseus and used in the treatment of cancers such as Hodgkin's lymphoma and Kaposi's sarcoma. Another example is paclitaxel isolated from species of the genus Taxus sp.…”

Nano-based formulations of curcumin: elucidating the potential benefits and future prospects in skin cancer

“…Treatments using curcumin and its analogues lead to autophagy in human melanoma cells as they arrest the G2/M phase of the cell cycle [15]. Furthermore, studies have revealed that these compounds decrease mTOR and AKT expression and this concept can be used as a probable target for the treatment of skin cancer [16]. Curcumin analogues explored for treating skin cancer are DMC [17], deketene curcumin [18], diarylpentanoid derivatives of curcumin [19], DM-1 [20], BDMC and 1,7-bis (4hydroxyphenyl)21,4,6-heptatrien-3-one (BHPHTO) [21] (figure 1).…”