Conventional treatment with taxanes (docetaxel-DTX or cabazitaxel-CBZ) increases survival rates of aggressive metastatic castration resistant prostate cancer (mCRPC) to some extent since the majority of patients acquire resistance to taxanes. The andrographolide analogue, 19-tert-butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1), has shown anticancer activity against various cancers. In this study, we investigated the effect of 3A.1 alone and in combination with DTX/CBZ against mCRPC and their mechanism of action. Exposure to 3A.1 alone exhibited a dose- and time-dependent antitumor activity in mCRPC. Chou-Talalay9s combination index (CI) values of all 3A.1+ TX combinations were less than 0.5, indicating synergism. Co-treatment of 3A.1 with TX reduced the required dose of DTX and CBZ (p0.7) genes, TRA2B and SF1, were associated with worse Gleason score and nodal metastasis status in prostate adenocarcinoma patients (PRAD-TCGA). Immunoblotting, COMET, and migration assays corroborated these findings. These results suggest that 3A.1 may be useful in increasing the anticancer efficacy of taxanes to treat aggressive PCa. Significance Statement The andrographolide analogue, 19-tert-butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1) has shown anticancer activity against metastatic Castration resistance and neuroendocrine variant prostate cancers (mCRPC/NEPC). Additionally, 3A.1 exhibited synergistic anticancer effect in combination with standard therapy docetaxel and cabazitaxel in mCRPC/NEPC. Post-treatment gene expression studies revealed that heat-shock proteins (Hsp70, Hsp40, Hsp27, Hsp90) and MAT2A are major players in the mechanism of 3A.1 action and drug response. Further, DNA damage, cell migration, hypoxia, and autophagy were the crucial pathways for the anticancer activity of 3A.1.

Background/Objectives: Personalized 3D-printed (3DP) metallic implants delivery systems are being explored to repair bone fractures, allowing the customization of medical implants that respond to individual patient needs, making it potentially more effective and of greater quality than mass-produced devices. However, challenges associated with postsurgical infections caused by bacterial adhesion remain a clinical issue. To address this, local antibiotic therapies are receiving extensive attention to minimize the risk of implant-related infections. This study investigated the use of amikacin (AMK), a broad-spectrum aminoglycoside antibiotic, incorporated onto 3D-printed 316L stainless steel implants using biodegradable polymer coatings of chitosan and poly lactic-co-glycolic acid (PLGA). Methods: This research examined different approaches to coat 3DP implants with amikacin. Various polymer-based coatings were studied to determine the optimal formulation based on the characteristics and release profile. The optimal formulation was performed on the antibacterial activity studies. Results: AMK-chitosan with PLGA coating implants controlled the rate of drug release for up to one month. The 3DP drug-loaded substrates demonstrated effective, concentration-dependent antibacterial activity against common infective pathogens. AMK-loaded substrates showed antimicrobial effectiveness for one week and inhibited bacteria significantly compared to the uncoated controls. Conclusions: This study demonstrated that 3DP metal surfaces coated with amikacin can provide customizable drug release profiles while effectively inhibiting bacterial growth. These findings highlight the potential of combining 3D printing with localized delivery strategies to prevent implant-associated infections and advance the development of personalized therapies.

Apoptosis induction and differentiation of promyelocytic leukemic cells into mature cells are major strategies for the drug-based treatment of leukemia. Lidamycin (LDM) which is a member of the enediyne antibiotic family exhibits extreme cytotoxicity. In the present study, the induction of apoptosis and differentiation in human chronic myeloid leukemia K562 cells by low concentrations of lidamycin were investigated. K562 cells were treated with lidamycin at various concentrations for 48 h, and accumulated in the metaphase as determined in previous experiments. Cell viability was determined using a Cell Counting Kit-8 (CCK-8) assay and the IC50 value of lidamycin was 0.1 +/- 3.2 nM. Induction of apoptosis was investigated morphologically by acridine orange/ethidium bromide (AO/EtBr) staining. Growth inhibition and apoptosis induction were observed in cells treated with low concentrations of lidamycin. In addition, western blot analysis revealed that treatment of the K562 cells with lidamycin at low concentrations upregulated the expression of caspase-8 and caspase-3. The induction of differentiation in human chronic myeloid leukemia K562 cells by lidamycin at low concentrations was also investigated. The nitroblue tetrazolium reduction ability of K562 cells was increased following treatment with lidamycin. Low concentrations of lidamycin triggered erythroid differentiation among K562 cells, indicated by morphological changes, increased hemoglobin content, and the expression of cell surface antigens such as CD71. Additionally the expression of GATA-binding factor 1 (GATA-1) protein in low concentration lidamycin-treated K562 cells was increased. The results of the present study suggest that a low-concentration lidamycin exerts effects on apoptosis and erythroid differentiation induction by increasing the expression of caspases and GATA-1 protein. Lidamycin may serve a positive role in relevant targeted chemotherapy and may represent a potential candidate for chronic myelogenous leukemia differentiation-inducing treatment.

Implant failures in orthopedic surgeries can occur due to inflammation, poor osteointegration, and biofilm formation. The local delivery of anti-inflammatory drugs is one of the potential solutions to address orthopedic implant failures caused by extensive inflammation, poor osteointegration, and biofilm formation. This study utilized a simple spray coating technique to deposit multilayer coatings of the anti-inflammatory drug meloxicam and PLGA on 3D printed 316L stainless steel implants. The implants were evaluated for their drug content, drug-polymer miscibility, static contact angle, corrosion resistance, in vitro release, cell adhesion, cell proliferation, and bacterial adhesion studies. The coatings aimed to improve osteointegration and reduce biofilm formation. The drug release studies demonstrated an initial burst release accompanied by sustained release for more than 30 days. The meloxicam-PLGA coated implants showed higher resistance to pitting corrosion, improved adhesion, and proliferation of human U2OS cells in comparison to uncoated implants. In addition, results from cell cytotoxicity studies confirmed that all the coatings are biocompatible and safe for in vivo application. The meloxicam-PLGA coated implants were also found to have significantly lower bacterial adhesion and biofilm formation compared to uncoated implants for both S. aureus ( p < 0.01) and S. pseudintermedius ( p < 0.01). The multilayer coatings developed in this study have the potential to improve adhesion at the implant-bone interface and thus might prevent implant rejections in patients undergoing orthopedic surgery. Moreover, this method can be applied to other drugs and polymers to address the issues related to implant failure, pain management, and surgical site infections. Graphical Abstract