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.

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

Cisplatin augments the anti-schistosomal effect of praziquantel in a schistosoma-infected cancer model

Schistosomiasis is the third most devastating tropical disease worldwide caused by blood flukes of the genus Schistosoma. Praziquantel (PZQ) is the drug of choice for treating all species of schistosomes. However, PZQ kills only adult Schistosoma worms, not immature stages. The inability of PZQ to abort early infection or prevent re-infection, and the lack of prophylactic effect prompt the need for novel drugs and strategies for the prevention of schistosomiasis. Tumor burden can be developed in Schistosoma-infected patients. The present study aimed to determine the host responses to mutual interaction between cancer, represented by Ehrlich ascites, and infection, represented by Schistosomiasis. Mice infected with Schistosoma and challenged with tumor 4-5 weeks later showed the same anti-schistosomal (worm and egg burden) and antitumor (total tumor cell count and mouse survival) parameters when compared to mice infected with Schistosoma alone or challenged with tumor cells alone. As expected, combinatorial treatment with PZQ and cisplatin of Schistosoma-infected mice that were challenged with tumor cell line decreased the tumor burden as well as the worm and egg burden after treatment as compared to the non-treated controls; while the worm burden and egg counts were significantly decreased (P <0.001) in treated group (VI) treated with cisplatin (0.5 mg/kg), group (VII) treated with cisplatin (2 mg/kg), group (VIII) treated with PZQ/ cisplatin (0.5 mg/kg) and group (IX) treated with PZQ / cisplatin (2 mg/kg) by 44.55% , 74%, 100% and 97.8% in worm burden, and by 47%, 78.7%, 96% and 97% in liver egg count , respectively than that of group (II) non treated S. mansoni infected alone and (IV) non treated S. mansoni/EAC alone. Also, Group IX caused a significant reduction (P <0.05) in worm burden than that of group VI. Also, total ascetic volume and the tumor cell counts in Ehrlich's ascites carcinoma (EAC)-cells were significantly decreased (P <0.001) in groups VIII and IX than that of the group (III) non-treated (EAC) inoculated alone. There was no mutual interaction between schistosomiasis infection and tumor burden. Also, whereas, PZQ did not affect on the antitumor parameters, cisplatin even at low doses had anti-schistosomal effects