A cost-utility analysis of BRCA1 and BRCA2 testing in high-risk breast cancer patients and family members in Thailand: a cost-effective policy in resource-limited settings.

Background: Screening for germline pathogenic BRCA1 or BRCA2 variants (gBRCA) in high-risk breast cancer patients is known to be cost-effective in high-income countries. Nationwide adoption of genetics testing in high-risk breast cancer population remains poor. Our study aimed to assess gBRCA health economics data in the middle-income country setting of Thailand. Methods: Decision tree and Markov model were utilized to assess cost-utility between the testing vs. no-testing groups from a societal and lifetime perspective and lifetime. We interviewed 264 patients with breast/ovarian cancer and their family members to assess relevant costs and quality of life using EQ-5D-5L. One-way sensitivity, probabilistic sensitivity (Monte Carlo simulation), and budget impact analyses were done to estimate the outcome under Thailand's Universal Health Coverage scheme. Results: The predicted lifetime cost and Quality-adjusted Life Years (QALY) for those with breast cancer were $13,788 and 10.22 in the testing group and $13,702 and 10.07 in the no-testing group. The incremental cost-effectiveness ratio for gBRCA testing in high-risk breast cancer patients was $573/QALY. The lifetime cost for the family members of those with gBRCA was $14,035 (QALY 9.99), while the no-testing family members group was $14,077 (QALY 9.98). Performing gBRCA testing in family members was cost-saving. Conclusion: Cost-utility analysis demonstrated a cost-effective result of gBRCA testing in high-risk breast cancer patients and cost-saving in familial cascade testing. The result was endorsed in the national health benefits package in 2022. Other middle-income countries may observe the cost-effective/cost-saving aspects in common genetic diseases under their national health schemes.

Norcycloartocarpin targets Akt and suppresses Akt-dependent survival and epithelial-mesenchymal transition in lung cancer cells.

In searching for novel targeted therapeutic agents for lung cancer treatment, norcycloartocarpin from Artocarpus gomezianus was reported in this study to promisingly interacted with Akt and exerted the apoptosis induction and epithelial-to-mesenchymal transition suppression. Selective cytotoxic profile of norcycloartocarpin was evidenced with approximately 2-fold higher IC50 in normal dermal papilla cells (DPCs) compared with human lung cancer A549, H460, H23, and H292 cells. We found that norcycloartocarpin suppressed anchorage-independent growth, cell migration, invasion, filopodia formation, and decreased EMT in a dose-dependent manner at 24 h, which were correlated with reduced protein levels of N-cadherin, Vimentin, Slug, p-FAK, p-Akt, as well as Cdc42. In addition, norcycloartocarpin activated apoptosis caspase cascade associating with restoration of p53, down-regulated Bcl-2 and augmented Bax in A549 and H460 cells. Interestingly, norcycloartocarpin showed potential inhibitory role on protein kinase B (Akt) the up-stream dominant molecule controlling EMT and apoptosis. Computational molecular docking analysis further confirmed that norcycloartocarpin has the best binding affinity of -12.52 kcal/mol with Akt protein at its critical active site. As Akt has recently recognized as an attractive molecular target for therapeutic approaches, these findings support its use as a plant-derived anticancer agent in cancer therapy.

Artocarpin Targets Focal Adhesion Kinase-Dependent Epithelial to Mesenchymal Transition and Suppresses Migratory-Associated Integrins in Lung Cancer Cells.

Focal adhesion kinase (FAK) controls several cancer aggressive potentials of cell movement and dissemination. As epithelial-mesenchymal transition (EMT) and the migratory-associated integrins, known influencers of metastasis, have been found to be linked with FAK activity, this study unraveled the potential pharmacological effect of artocarpin in targeting FAK resulting in the suppression of EMT and migratory behaviors of lung cancer cells. Treatment with artocarpin was applied at concentrations of 0-10 µM, and the results showed non-cytotoxicity in lung cancer cell lines (A549 and H460), normal lung (BEAS-2B) cells and primary metastatic lung cancer cells (ELC12, ELC16, and ELC20). We also found that artocarpin (0-10 µM) had no effect on cell viability, proliferation, and migration in BEAS-2B cells. For metastasis-related approaches, artocarpin significantly inhibited cell migration, invasion, and filopodia formation. Artocarpin also dramatically suppressed anchorage-independent growth, cancer stem cell (CSC) spheroid formation, and viability of CSC-rich spheroids. For molecular targets of artocarpin action, computational molecular docking revealed that artocarpin had the best binding affinity of -8.0 kcal/mol with FAK protein. Consistently, FAK-downstream proteins, namely active Akt (phosphorylated Akt), active mTOR (phosphorylated mTOR), and Cdc42, and EMT marker and transcription factor (N-cadherin, Vimentin, and Slug), were found to be significantly depleted in response to artocarpin treatment. Furthermore, we found the decrease of Caveolin-1 (Cav-1) accompanied by the reduction of integrin-αν and integrin-ß3. Taken together, these findings support the anti-metastasis potentials of the compound to be further developed for cancer therapy.

Suppressing Cdk5 Activity by Luteolin Inhibits MPP+-Induced Apoptotic of Neuroblastoma through Erk/Drp1 and Fak/Akt/GSK3ß Pathways.

Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons. The cause of PD is still unclear. Oxidative stress and mitochondrial dysfunction have been linked to the development of PD. Luteolin, a non-toxic flavonoid, has become interested in an alternative medicine, according to its effects on anti-oxidative stress and anti-apoptosis, although the underlying mechanism of luteolin on PD has not been fully elucidated. This study aims to investigate whether luteolin prevents neurotoxicity induction by 1-methyl-4-phenylpyridinium iodide (MPP+), a neurotoxin in neuroblastoma SH-SY5Y cells. The results reveal that luteolin significantly improved cell viability and reduced apoptosis in MPP+-treated cells. Increasing lipid peroxidation and superoxide anion (O2-), including mitochondrial membrane potential (Δψm) disruption, is ameliorated by luteolin treatment. In addition, luteolin attenuated MPP+-induced neurite damage via GAP43 and synapsin-1. Furthermore, Cdk5 is found to be overactivated and correlated with elevation of cleaved caspase-3 activity in MPP+-exposed cells, while phosphorylation of Erk1/2, Drp1, Fak, Akt and GSK3ß are inhibited. In contrast, luteolin attenuated Cdk5 overactivation and supported phosphorylated level of Erk1/2, Drp1, Fak, Akt and GSK3ß with reducing in cleaved caspase-3 activity. Results indicate that luteolin exerts neuroprotective effects via Cdk5-mediated Erk1/2/Drp1 and Fak/Akt/GSK3ß pathways, possibly representing a potential preventive agent for neuronal disorder.

Ovalitenone Inhibits the Migration of Lung Cancer Cells via the Suppression of AKT/mTOR and Epithelial-to-Mesenchymal Transition.

Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. METHODS: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. RESULTS: Ovalitenone was used at concentrations of 0-200 µM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. CONCLUSIONS: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.

Ephemeranthol A Suppresses Epithelial to Mesenchymal Transition and FAK-Akt Signaling in Lung Cancer Cells.

BACKGROUND/AIM: Epithelial to mesenchymal transition (EMT) is a cellular process that facilitates cancer metastasis. Therefore, therapeutic approaches that target EMT have garnered increasing attention. The present study aimed to examine the in vitro effects of ephemeranthol A on cell death, migration, and EMT of lung cancer cells. MATERIALS AND METHODS: Ephemeranthol A was isolated from Dendrobium infundibulum. Non-small cell lung cancer cells H460 were treated with ephemeranthol A and apoptosis was evaluated by Hoechst 33342 staining. Anoikis resistance was determined by soft agar assay. Wound healing assay was performed to test the migration. The regulatory proteins of apoptosis and cell motility were determined by western blot. RESULTS: Treatment with ephemeranthol A resulted in a concentration-dependent cell apoptosis. At non-toxic concentrations, the compound could inhibit anchorage-independent growth of the cancer cells, as indicated by the decreased colony size and number. Ephemeranthol A also exhibited an inhibitory effect on migration. We further found that ephemeranthol A exerts its antimetastatic effects via inhibition of EMT, as indicated by the markedly decrease of N-cadherin, vimentin, and Slug. Furthermore, the compound suppressed the activation of focal adhesion kinase (FAK) and protein kinase B (Akt) proteins, which are key regulators of cell migration. As for the anticancer activity, ephemeranthol A induced apoptosis by decreasing Bcl-2 followed by the activation of caspase 3 and caspase 9. CONCLUSION: The pro-apoptotic and anti-migratory effects of ephemeranthol A on human lung cancer cells support its use for the development of novel anticancer therapies.

Benzoxazine Dimer Analogue Targets Integrin ß3 in Lung Cancer Cells and Suppresses Anoikis Resistance and Migration.

BACKGROUND/AIM: Certain integrins including integrin ß3 facilitate movement and survival of metastatic cancer cells. We examined whether benzoxazine dimer analogue N,N-bis(5-ethyl-2-hydroxybenzyl) methylamine (HM) has anti-metastatic effects. MATERIALS AND METHODS: Cell viability was examined by the 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. Wound healing and phalloidin-rhodamine assays were performed to evaluate the migration and filopodia formation, respectively. Anoikis resistance was studied by anchorage-independent growth assay. The expression of proteins regulating migration were examined by western blot. RESULTS: HM treatment significantly inhibited growth and survival of detached lung cancer cells as indicated by the reduced colony number and size of anchorage-independent growth analysis. HM inhibited cell migration and suppressed filopodia formation. Protein analysis indicated that the compound dramatically decreased integrin ß3 and its related downstream proteins including active focal adhesion kinase (FAK) and active protein kinase B (AKT); however, integrin ß1 and α5 were found to be unaltered. CONCLUSION: HM shows a potential in targeting integrin ß3 and could be a good candidate for further developed as an anti-metastatic therapy.

C-myc Contributes to Malignancy of Lung Cancer: A Potential Anticancer Drug Target.

Emerging evidence has provided important information on oncoproteins involved in cancer initiation, progression, metastasis, and resistance to current therapies. C-myc, one of the critical oncoproteins, has been shown to be implicated in enhancing the aggressiveness of many cancers, mainly through its ability to increase cancer cell growth and cellular survival mechanisms. Despite the more precise and earlier detection and the availability of better therapies, lung cancer remains the most dreadful cancer as it causes high mortality rate with relatively poor treatment success. In lung cancer, C-myc is frequently dysregulated and associated with unfavorable patient survival. C-myc plays a role in regulation of lung cancer cell behaviors including growth, resistance, death, and dissemination through the activation of cell cycle driving proteins, an increase in the cellular levels of anti-apoptotic proteins, and the modulation of metabolism. Besides, C-myc has been shown to be important for cancer stem cell (CSC) properties. Taken together, targeting as well as inhibiting C-myc could provide promising means for resolving lung cancer. This review emphasizes on the molecular mechanism by which C-myc influences lung cancer growth, metastasis, drug resistance, and CSC maintenance, and suggests the target proteins that may benefit drug discovery and design.