Bacteria-driven cancer therapy: Exploring advancements and challenges.

Cancer, a serious fatal disease caused by the uncontrolled growth of cells, is the biggest challenge flagging around medicine and health fields. Conventionally, various treatments-based strategies such as radiotherapy, chemotherapy, and alternative cancer therapies possess drugs that cannot reach the cancerous tissues and make them toxic to noncancerous cells. Cancer immunotherapy has made outstanding achievements in reducing the chances of cancer. Our considerable attention towards cancer-directed immune responses and the mechanisms behind which immune cells kill cancer cells have progressively been helpful in the advancement of new therapies. Among them, bacteria-based cancer immunotherapy has achieved much more attention due to smart and robust mechanisms in activating the host anti-tumor response. Moreover, bacterial-based therapy can be utilized as a single monotherapy or in combination with multiple anticancer immunotherapies to accelerate productive clinical results. Herein, we comprehensively reviewed recent advancements, challenges, and future perspectives in developing bacterial-based cancer immunotherapies.

Latcripin-7A from Lentinula edodes C91-3 induces apoptosis, autophagy, and cell cycle arrest at G1 phase in human gastric cancer cells via inhibiting PI3K/Akt/mTOR signaling.

Gastric cancer (G.C) is one of the most lethal cancer types worldwide. Current treatment requires surgery along with chemotherapy, which causes obstacles for speedy recovery. The discovery of novel drugs is needed for better treatment of G.C with minimum side effects. Latcripin-7A (LP-7A) is a newly discovered peptide extracted from Lentinula edodes. It is recently studied for its anti-cancer activity. In this study, LP-7A was modeled using a phyre2 server. Anti-proliferation effects of LP-7A on G.C cells were examined via CCK-8, colony formation, and morphology assay. Apoptosis of LP-7A treated G.C cells was evaluated via Hoechst Stain, western blot and flow cytometry. Autophagy was assessed via acridine orange staining and western blot. The cell cycle was assessed via flow cytometry assay and western blot. Pathway was studied via western blot and STRING database. Anti-migratory effects of LP-7A treated G.C cells were analyzed via wound healing, western blot, and migration and invasion assay. LP-7A effectively inhibited the growth of G.C cells by inhibiting the PI3K/Akt/mTOR pathway. G.C cells treated with LP-7A arrested the cell cycle at the G1 phase, contributing to the inhibition of migration and invasion. Furthermore, LP-7A induced apoptosis and autophagy in gastric cancer cells. These results indicated that LP-7A is a promising anti-cancer agent. It affected the proliferation and growth of G.C cells (SGC-7901 and BGC-823) by inducing apoptosis, autophagy, and inhibiting cell cycle at the G1 phase in G.C cells.

Molecular mechanisms of anticancer activities of polyphyllin VII.

Cancer is the leading cause of mortality in the world. The major therapies for cancer treatment are chemotherapy, surgery, and radiation therapy. All these therapies expensive, toxic and show resistance. The plant-derived compounds are considered safe, cost-effective and target cancer through different pathways. In these pathways include oxidative stress, mitochondrial dependent and independent, STAT3, NF-kB, MAPKs, cell cycle, and autophagy pathways. One of the new plants derived compounds is Polyphyllin VII (PPVII), which target cancer through different molecular mechanisms. In literature, there is a review gap of studies on PPVII; therefore in the current review, we summarized the available studies on PPVII to provide a base for future research.

Inhibition of JNK-Mediated Autophagy Promotes Proscillaridin A- Induced Apoptosis via ROS Generation, Intracellular Ca+2 Oscillation and Inhibiting STAT3 Signaling in Breast Cancer Cells.

Breast cancer is the most heterogenous cancer type among women across the world. Despite concerted efforts, breast cancer management is still unsatisfactory. Interplay between apoptosis and autophagy is an imperative factor in categorizing therapeutics for cancer treatment. Proscillaridin A (PSD-A), a well-known cardiac glycoside used for cardiac arrest and arrythmias, has been unveiled in many cancer types but the underlying mechanism for apoptosis and autophagy in breast cancer is not fully understood. In our study, PSD-A restricted cell growth, inhibited STAT3 activation and induced apoptosis and autophagy in breast cancer cells via ROS generation and Ca+2 oscillation. Pretreatment of NAC and BAPTA-AM restored PSD-A induced cellular events in breast cancer cells. PSD-A induced apoptosis via DNA fragmentation, caspase-cascade activation, PARP cleavage, mitochondrial dysfunction, Bax/Bcl-2 proteins modulation and ER chaperone GRP78 inhibition along with decreased phosphorylation of ERK1/2. Inhibition of STAT3 activation was found to be associated with decreased phosphorylation of SRC. Moreover, PSD-A induced events of autophagy i.e. conversion of LC3-I to LC3-II, and Atg3 expression via JNK activation and decreased mTOR and AKT phosphorylation. In this study, pretreatment of SP600125, a JNK inhibitor, reduced autophagy and enhanced STAT3 inhibition and apoptosis. Additionally, SB203580, a commercial p38 inhibitor, stimulated STAT3 activation and improved autophagic events rate in breast cancer cells, displaying the role of the MAPK signaling pathway in interplay between apoptosis and autophagy. Our data suggest that the rate of apoptotic cell death is improved by blocking JNK-induced autophagy in PSD-A treated MCF-7 and MDA-MB-231 breast cancer cells.

Latcripin-7A, derivative of Lentinula edodes C91-3, reduces migration and induces apoptosis, autophagy, and cell cycle arrest at G1 phase in breast cancer cells.

Due to the high mortality rate and an increase in breast cancer incidence, it has been challenging for researchers to come across an effective chemotherapeutic strategy with minimum side effects. Therefore, the need for the development of effective chemotherapeutic drugs is still on the verge. Consequently, we approached a new mechanism to address this issue. The naturally available peptide named latcripin-7A (LP-7A), extracted from a mushroom called Lentinula edodes, provided us promising results in terms of growth arrest, apoptosis, and autophagy in breast cancer cells (MCF-7 and MDA-MB-231). Expressions of protein markers for apoptosis, autophagy, and cell cycle were confirmed via Western blot analysis. Migration and invasion assays were performed to analyze the anti-migratory and anti-invasive properties of LP-7A, while cell cycle analysis was performed via flow cytometry to evaluate its affect over cell growth. Supportive assays were performed like acridine orange, Hoechst 33258 stain, DNA fragmentation, and mitochondrial membrane potential (MMP) to further confirm the anticancer effect of LP-7A on breast cancer cell lines. It is concluded that LP-7A effectively reduces migration and promotes apoptosis as well as autophagy in MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell growth arrest at G0/G1 phase and decreasing mitochondrial membrane potential without adverse effects on MCF-10A normal breast cells. KEY POINTS: • In this study, we have investigated the anti-cancer activity of novel latcripin-7A (LP-7A), a protein extracted as a result of de novo characterization of Lentinula edodes C91-3. • We conclude in our research work that LP-7A can initiate diverse cell death-related events, i.e., apoptosis and autophagy in both triple-positive and triple-negative breast cancer cell lines by interacting with different nodes of cellular signaling that can further be investigated in vivo to gain a better understanding.

Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells.

PURPOSE: Breast cancer is the most common malignancy among women across the globe. Despite concerted efforts to improve the prevailing treatment modalities, the overall prognosis of breast cancer remains unsatisfactory. Recently, antiproliferative activity of Brevilin A (Brv-A), a sesquiterpene lactone compound of Centipeda minima, has been unveiled in various cancer types. Here, we have explored anticancer activity of Brv-A in MCF-7 breast carcinoma cells by targeting various pathways. MATERIALS AND METHODS: Cell proliferation rate was determined by CCK-8 and clonogenic assay. Cellular morphological changes were observed under phase contrast microscope while calcein-AM and PI was used for live/dead assay. Cell cycle assay was performed by flow cytometry. Apoptotic cell percentage was determined by Hoechst 33258 staining and flow cytometric analysis. ROS generation and mitochondrial membrane potential were measured using commercially available kits while protein expression was measured by Western blotting. RESULTS: In our study, Brv-A exerted antiproliferative effect through mitotic arrest at G2/M phase of cell cycle and induced apoptosis in MCF-7 cells in a dose-dependent manner. Induction of apoptosis by Brv-A was found to be associated with ROS generation by targeting NOX2 and NOX3, mitochondrial dysfunction (MMP dissipation and Bcl-2 family proteins modulation), DNA fragmentation, JNK and p38 MAPK activation, endoplasmic reticulum (ER) stress by increasing Bip/GRP78, ATF4 and CHOP protein expressions and inhibition of STAT3 activation via decreased phosphorylation of JAK2 and SRC. Pretreatment of NAC, a ROS scavenger, partially reversed the aforesaid cellular events indicating ROS generation as the primary event to modulate cellular targets for induction of apoptosis. Besides, Brv-A has also been documented for inhibition of cell migration via decrease in COX-2 and MMP-2 expression. CONCLUSION: Taken together, Brv-A induces G2/M phase arrest, ROS-dependent apoptosis, ER stress, mitochondrial dysfunction and inhibits STAT3 activation in MCF-7 cells signifying it to be one of the potential anticancer therapeutics in future.

LP1 from Lentinula edodes C91-3 Induces Autophagy, Apoptosis and Reduces Metastasis in Human Gastric Cancer Cell Line SGC-7901.

Present study aimed to elucidate the anticancer effect and the possible molecular mechanism underlying the action of Latcripin 1 (LP1), from the mushroom Lentinula edodes strain C91-3 against gastric cancer cell lines SGC-7901 and BGC-823. Cell viability was measured by Cell Counting Kit-8 (CCK-8); morphological changes were observed by phase contrast microscope; autophagy was determined by transmission electron microscope and fluorescence microscope. Apoptosis and cell cycle were assessed by flow cytometer; wound-healing, transwell migration and invasion assays were performed to investigate the effect of LP1 on gastric cancer cell's migration and invasion. Herein, we found that LP1 resulted in the induction of autophagy by the formation of autophagosomes and conversion of light chain 3 (LC3I into LC3II. LP1 up-regulated the expression level of autophagy-related gene (Atg7, Atg5, Atg12, Atg14) and Beclin1; increased and decreased the expression level of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) proteins respectively, along with the activation of Caspase-3. At lower-doses, LP1 have shown to arrest cells in the S phase of the cell cycle and decreased the expression level of matrix metalloproteinase MMP-2 and MMP-9. In addition, it has also been shown to regulate the phosphorylation of one of the most hampered gastric cancer pathway, that is, protein kinase B/mammalian target of rapamycin (Akt/mTOR) channel and resulted in cell death. These findings suggested LP1 as a potential natural anti-cancer agent, for exploring the gastric cancer therapies and as a contender for further in vitro and in vivo investigations.

Antibacterial and anti-biofilm activity of the lipid extract from Mantidis ootheca on Pseudomonas aeruginosa.

The aim of this study is to assess the antibacterial and anti-biofilm properties of the lipid extract from Mantidis ootheca against the gentamycin resistant Pseudomonas aeruginosa. The chemical composition of the lipid extract and its relative proportion were determined using the technique of gas chromatography coupled with mass spectrometry (GC-MS). Antibacterial susceptibility tests were performed using a disc diffusion assay and the minimum inhibition concentration (MIC) was determined by way of the agar dilution method. The anti-biofilm test was carried out with crystal violet staining and scanning electron microscopy (SEM). There were 16 compounds detected, and the most abundant components were sesquiterpenoids, monoterpenes, and trace aromatic compounds. The MIC for P. aeruginosa was 4 mg/ml and the eradication effect on preformed biofilms was established and compared with a ciprofloxacin control. The results of our study indicated that a lipid extract from M. ootheca could be used as a topical and antibacterial agent with anti-biofilm activity in the future.