Antitumor effect of culinary-medicinal oyster mushroom, Pleurotus ostreatus (Jacq.: Fr.) P. Kumm., Derived protein fraction on tumor-bearing mice models

Previously, we reported the in vitro anticancer and immunomodulatory effect of a protein fraction designated as Cibacron Blue Affinity Purified Protein (CBAEP) obtained from the culinary-medicinal oyster mushroom, Pleurotus ostreatus. In the present study, we investigated the in vivo antitumor potential of CBAEP in different tumor-bearing mice models and studied the detailed mechanism of tumor regression in Dalton Lymphoma (DL)-bearing mice. The lethal dose (LD50) of CBAEP was found to be 55 mg/kg body weight and sublethal doses (5 mg/kg and 10 mg/kg body weight) showed a prolonged tumor survival time in DL, Sarcoma-180 and B16F0 melanoma tumor-bearing mice. Further, CBAEP reduced about 35.68 and 51.43% DL cell growth in 5 and 10 mg/kg body weight, respectively. The in vivo CBAEP treatment showed an apoptotic feature as demonstrated in morphological study and sub-G0/G1 population in cell cycle and Western blot of DL cells. CBAEP also activated immunosuppression condition in DL tumor-bearing host. It also stimulated immune cells in the presence of nonspecific immunostunulator (LPS and ConA) ex vivo as well as enhanced Th1 response with production of TNF-α, IFN-γ and IL-2. Moreover, it activated tumor-associated macrophages and NK cells. The present findings revealed the potent antitumor property of CBAEP, which might help in developing a new anticancer drug

Chemical diversity of dietary phytochemicals and their mode of chemoprevention

Despite the advancement in prognosis, diagnosis and treatment, cancer has emerged as the second leading cause of disease-associated death across the globe. With the remarkable application of synthetic drugs in cancer therapy and the onset of therapy-associated adverse effects, dietary phytochemicals have been materialized as potent anti-cancer drugs owing to their antioxidant, apoptosis and autophagy modulating activities. With dynamic regulation of apoptosis and autophagy in association with cell cycle regulation, inhibition in cellular proliferation, invasion and migration, dietary phytochemicals have emerged as potent anti-cancer pharmacophores. Dietary phytochemicals or their synthetic analogous as individual drug candidates or in combination with FDA approved chemotherapeutic drugs have exhibited potent anti-cancer efficacy. With the advancement in cancer therapeutics, dietary phytochemicals hold high prevalence for their use as precision and personalized medicine to replace conventional chemotherapeutic drugs. Hence, keeping these perspectives in mind, this review focuses on the diversity of dietary phytochemicals and their molecular mechanism of action in several cancer subtypes and tumor entities. Understanding the possible molecular key players involved, the use of dietary phytochemicals will thrive a new horizon in cancer therapy

Blockade of autophagy enhances proapoptotic potential of BI-69A11, a novel Akt inhibitor, in colon carcinoma

BI-69A11, novel Akt inhibitor, is currently drawing much attention due to its intriguing effect in inducing apoptosis in melanoma, breast, prostate and colon cancer. However, earlier reports reveal that PI3K/Akt/ mTOR inhibitors promote autophagy at the early stage as a survival mechanism that might affect its apoptotic potential. It is necessary to investigate whether BI-69A11 mediated apoptosis is associated with autophagy for enhancing its therapeutic efficacy. Here, we found that BI-69A11 induced autophagy at earlier time point through the inhibition of Akt/mTOR/p70S6 kinase pathway. Dose-dependent and time-dependent conversion of LC3-I to LC3-II, increased accumulation of LC3-GFP dots in cytoplasm and increase in other autophagic markers such as Beclin-1, firmly supported the fact that BI-69A11 induces autophagy. Atg5, Atg7 and Beclin-1 siRNA mediated genetic attenuation and pre-treatment with pharmacological inhibitor 3-MA and CQ diminished the autophagy and increased the propensity of cell death towards apoptosis. It was also suggested that BI-69A11 mediated interaction between Akt, HSP-90 and Beclin-1 maintained the fine balance between autophagy and apoptosis. Interaction between Beclin-1 and HSP90 is one of the prime causes of induction of autophagy. Here, we also generated a novel combination therapy by pretreatment with CQ that inhibited the autophagy and accelerated the apoptotic potential of BI-69A11. In summary; our findings suggest that induction of autophagy lead to the resistance of colon cancer towards BI-69A11 mediated apoptosis

Oxidative stress-induced autophagy compromises stem cell viability

Stem cell therapies have emerged as a promising treatment strategy for various diseases characterized by ischemic injury such as ischemic stroke. Cell survival after transplantation remains a critical issue. We investigated the impact of oxidative stress, being typically present in ischemically challenged tissue, on human dental pulp (hDPSC) and mesenchymal stem cell (hMSC). We used oxygen-glucose deprivation (OGD) to induce oxidative stress in hDPSC and hMSC. OGD-induced generation of O2 •− or H2O2 enhanced autophagy by inducing the expression of Activating Molecule in BECN1-Regulated Autophagy Protein 1 (Ambra1) and Beclin1 in both cell types. However, hDPSC and hMSC pre-conditioning using reactive oxygen species (ROS) scavengers significantly repressed the expression of Ambra1 and Beclin1 and inactivated autophagy. O2 •− or H2O2 acted upstream of autophagy, and the mechanism was unidirectional. Further, our findings revealed ROS-p38-Erk1/2 involvement. Pre-treatment with selective inhibitors of p38 and Erk1/2 pathways (SB202190 and PD98059) reversed OGD effects on the expression of Ambra1 and Beclin1, suggesting that these pathways induced oxidative stress-mediated autophagy. SIRT3 depletion was found to be associated with increased oxidative stress and activation of p38 and Erk1/2 MAPKs pathways. Global ROS inhibition by NAC or a combination of polyethylene glycol-superoxide dismutase (PEG-SOD) and polyethylene glycol-catalase (PEG-catalase) further confirmed that O2 •− or H2O2 or a combination of both impacts stems cell viability by inducing autophagy. Further, autophagy inhibition by 3-Methyladenine (3-MA) significantly improved hDPSC viability. These findings contribute to a better understanding of post-transplantation hDPSC and hMSC death and may inform strategies to minimize therapeutic cell loss under oxidative stress