Lithocholic acid (LCA) is a secondary bile acid that is selectively toxic to human neuroblastoma, breast and prostate cancer cells, whilst sparing normal cells. We previously reported that LCA inhibited cell viability and proliferation and induced apoptosis and necrosis of androgen-dependent LNCaP and androgen-independent PC-3 human prostate cancer cells. In the present study, we investigated the roles of endoplasmic reticulum (ER) stress, autophagy and mitochondrial dysfunction in the toxicity of LCA in PC-3 and autophagy deficient, androgen-independent DU-145 cells. LCA induced ER stress-related proteins, such as CCAAT-enhancer-binding protein homologous protein (CHOP), and the phosphorylation of eukaryotic initiation factor 2-alpha (p-eIF2α) and c-Jun N-terminal kinases (p-JNK) in both cancer cell-types. The p53 upregulated modulator of apoptosis (PUMA) and B cell lymphoma-like protein 11 (BIM) levels were decreased at overtly toxic LCA concentrations, although PUMA levels increased at lower LCA concentrations in both cell lines. LCA induced autophagy-related conversion of microtubule-associated proteins 1A/1B light chain 3B (LC3BI–LC3BII), and autophagy-related protein ATG5 in PC-3 cells, but not in autophagy-deficient DU-145 cells. LCA (>10 µM) increased levels of reactive oxygen species (ROS) concentration-dependently in PC-3 cells, whereas ROS levels were not affected in DU-145 cells. Salubrinal, an inhibitor of eIF2α dephosphorylation and ER stress, reduced LCA-induced CHOP levels slightly in PC-3, but not DU-145 cells. Salubrinal pre-treatment increased the cytotoxicity of LCA in PC-3 and DU-145 cells and resulted in a statistically significant loss of cell viability at normally non-toxic concentrations of LCA. The late-stage autophagy inhibitor bafilomycin A1 exacerbated LCA toxicity at subtoxic LCA concentrations in PC-3 cells. The antioxidant α-tocotrienol strongly inhibited the toxicity of LCA in PC-3 cells, but not in DU-145 cells. Collectively, although LCA induces autophagy and ER stress in PC-3 cells, these processes appear to be initially of protective nature and subsequently consequential to, but not critical for the ROS-mediated mitochondrial dysfunction and cytotoxicity of LCA. The full mechanism of LCA-induced mitochondrial dysfunction and cytotoxicity in the similarly sensitive DU-145 cells remains to be elucidated.

Concerns about such issues may lead to reluctance to initiate therapy or premature discontinuation. Counseling and understanding of women's concerns and experiences using Depo-Provera is important and could help health care providers redesign counseling strategies to improve contraceptive continuation and improve patient adherence.

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Bioactive compounds extracted from marine organisms showed several biological activities. The present study is an extension of our earlier studies where we assessed the antiproliferative and pro-apoptotic activities of ethanol, methylene chloride, ethyl acetate, acetone, and chloroform crude extracts of sponges: Negombata magnifica (NmE) and Callyspongia siphonella (CsE) against cancer cells. Herein, we are extending our previous findings on both sponge species depending on an alternative methanol extraction method with more advanced molecular biochemical insights as additional proof for anticancer and antimicrobial activity of N. magnifica and C. siphonella. Therefore, sponge specimens were collected during winter 2020 from the Dahab region at the Gulf of Aqaba. Each sponge was macerated with methanol to obtain the crude extracts; NmE and CsE. GC–MS analysis presented a total of 117 chemical compounds; 37 bioactive, 11 represented previously as constituents for a natural organism, and 69 had no biological activities. NmE dose-dependently inhibited the growth of HepG2, MCF-7, and Caco-2 carcinoma cell lines compared to CsE, which unfortunately has no antiproliferative activity against the same cancer cells. NmE was found to induce G0/G1 cell cycle arrest in HepG2 cells with its inhibition for CDK6, Cyclins D1, and E1 in HepG2, MCF-7, and Caco-2 cells. NmE also activated ROS production in HepG2 cells and induced apoptosis in HepG2, MCF-7, and Caco-2 cells via an increase in pro-apoptotic protein Bax, caspase-3, and cleavage PARP, and a decrease in anti-apoptotic protein BCL2. Unlike its anticancer potential, CsE exhibited clear superior results as an antimicrobial agent with a wider range against six microbial strains, whereas NmE showed a positive antibacterial activity against only two strains.