Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

Abstract

Cancer is a complex devastating disease with enormous treatment challenges, including chemo- and radiotherapeutic resistance. Combination therapy demonstrated a promising strategy to target hard-to-treat cancers and sensitize cancer cells to conventional anti-cancer drugs such as doxorubicin. This study aimed to establish molecular profiling and therapeutic efficacy assessment of chloroquine and/or tioconazole (TIC) combination with doxorubicin (DOX) as anew combination model in MCF-7 breast cancer. The drugs are tested against apoptotic/autophagic pathways and related redox status. Molecular docking revealed that chloroquine (CQ) and TIC could be potential PI3K and ATG4B pathway inhibitors. Combination therapy significantly inhibited cancer cell viability, PI3K/AkT/mTOR pathway, and tumor-supporting autophagic flux, however, induced apoptotic pathways and altered nuclear genotoxic feature. Our data revealed that the combination cocktail therapy markedly inhibited tumor proliferation marker (KI-67) and cell growth, along with the accumulation of autophagosomes and elevation of LC3-II and p62 levels indicated autophagic flux blockage and increased apoptosis. Additionally, CQ and/or TIC combination therapy with DOX exerts its activity on the redox balance of cancer cells mediated ROS-dependent apoptosis induction achieved by GPX3 suppression. Besides, Autophagy inhibition causes moderately upregulation in ATGs 5,7 redundant proteins strengthened combinations induced apoptosis, whereas inhibition of PI3K/AKT/mTOR pathway with Beclin-1 upregulation leading to cytodestructive autophagy with overcome drug resistance effectively in curing cancer. Notably, the tumor growth inhibition and various antioxidant effects were observed in vivo. These results suggest CQ and/or TIC combination with DOX could act as effective cocktail therapy targeting autophagy and PI3K/AKT/mTOR pathways in MCF-7 breast cancer cells and hence, sensitizes cancer cells to doxorubicin treatment and combat its toxicity.

Integrated Metabolomics and Network Pharmacology to Establish the Action Mechanism of Qingrekasen Granule for Treating Nephrotic Syndrome

“…These results indicate that QRKSG protects renal tubular cells against ADR-induced renal damage. The findings are consistent with previous research ( Lieberthal and Levine, 2009 ; Kaushal et al, 2020 ; Zhou et al, 2020 ; Bhosale et al, 2021 ; El-Gowily et al, 2021 ), and the relevant target graphs are shown in Supplementary Figure S3 . Therefore, QRKSG could promote autophagy and anti-apoptosis through the expression of AKT1, CASP3, BCL2L1, and mTOR, thereby conferring protection to the podocytes and maintaining renal function and tubular homeostasis.…”

HSP90AA1 promotes the inflammation in human gingival fibroblasts induced by Porphyromonas gingivalis lipopolysaccharide via regulating of autophagy

“…It has been reported that the levels of RNA and protein expression of ATG5 increased in Pg-LPS induced HGFs [ 40 ]. El-Gowily have confirmed that up-regulation of Beclin-1 could produce disruptive autophagy [ 41 ]. Pg-LPS significantly increased the proteins levels of ATG5, Beclin1, and p-NF-κB p65/NF-κB p65 in HGFs, and the ratio of LC3-II/LC3-I was increased in dose-dependent manner.…”

HSP90AA1 promotes the inflammation in human gingival fibroblasts induced by Porphyromonas gingivalis lipopolysaccharide via regulating of autophagy

“…It has been reported that the level of RNA and protein expression of ATG5 is increased in HGF stimulated by LPS [39] . El-Gowily have con rmed that up regulation of Beclin-1 could produce disruptive autophagy [40] . Our research is consistent with the above description.…”