Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth

by Selleckchem | Jul 22 2023

Glioblastomas are a highly aggressive cancer type which respond poorly to current pharmaceutical treatments, thus novel therapeutic approaches need to be investigated. One such approach involves the use of the bioactive natural product Tanshinone IIA (T2A) derived from the Chinese herb Danshen, where mechanistic insight for this anti-cancer agent is needed to validate its use. Here, we employ a tractable model system, Dictyostelium discoideum, to provide this insight. T2A potently inhibits cellular proliferation of Dictyostelium, suggesting molecular targets in this model. We show that T2A rapidly reduces phosphoinositide 3 kinase (PI3K) and protein kinase B (PKB) activity, but surprisingly, the downstream complex mechanistic target of rapamycin complex 1 (mTORC1) is only inhibited following chronic treatment. Investigating regulators of mTORC1, including PKB, tuberous sclerosis complex (TSC), and AMP-activated protein kinase (AMPK), suggests these enzymes were not responsible for this effect, implicating an additional molecular mechanism of T2A. We identify this mechanism as the increased expression of sestrin, a negative regulator of mTORC1. We further show that combinatory treatment using a PI3K inhibitor and T2A gives rise to a synergistic inhibition of cell proliferation. We then translate our findings to human and mouse-derived glioblastoma cell lines, where both a PI3K inhibitor (Paxalisib) and T2A reduces glioblastoma proliferation in monolayer cultures and in spheroid expansion, with combinatory treatment significantly enhancing this effect. Thus, we propose a new approach for cancer treatment, including glioblastomas, through combinatory treatment with PI3K inhibitors and T2A.

Comments:

The passage you provided describes a study that explores the potential use of Tanshinone IIA (T2A), a natural product derived from the Chinese herb Danshen, as a therapeutic agent for glioblastomas, a highly aggressive type of cancer. The study investigates the molecular mechanisms underlying the anti-cancer effects of T2A using a model system called Dictyostelium discoideum and then validates these findings in human and mouse-derived glioblastoma cell lines.

The researchers found that T2A effectively inhibits cellular proliferation in Dictyostelium, indicating that it may have molecular targets in this model system. They discovered that T2A rapidly reduces the activity of phosphoinositide 3 kinase (PI3K) and protein kinase B (PKB), but interestingly, the downstream mechanistic target of rapamycin complex 1 (mTORC1) is only inhibited after chronic treatment with T2A. To understand this effect, the researchers investigated the involvement of other regulators of mTORC1, including PKB, tuberous sclerosis complex (TSC), and AMP-activated protein kinase (AMPK). However, these enzymes were not found to be responsible for the inhibition of mTORC1, suggesting the involvement of an additional molecular mechanism of T2A. The researchers identified this mechanism as the increased expression of sestrin, a negative regulator of mTORC1.

Furthermore, the study demonstrated that combination treatment with a PI3K inhibitor and T2A resulted in a synergistic inhibition of cell proliferation in Dictyostelium. This finding suggests that the combination of these two agents may enhance the anti-cancer effects. The researchers then extended their investigation to human and mouse-derived glioblastoma cell lines. In both monolayer cultures and spheroid expansion, treatment with both a PI3K inhibitor (Paxalisib) and T2A reduced glioblastoma proliferation. Importantly, the combination treatment showed even greater effectiveness in inhibiting glioblastoma growth.

Based on these findings, the study proposes a new approach for cancer treatment, specifically for glioblastomas, through the combination of PI3K inhibitors and T2A. The study provides mechanistic insights into the anti-cancer effects of T2A and highlights its potential as a therapeutic agent in combination with existing pharmaceutical treatments for glioblastoma and possibly other cancer types.