Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high mortality but limited therapeutic options. Epigenetic regulations including DNA methylation and histone modification ...control gene expressions and play a crucial role during tumorigenesis. G9a, also known as EHMT2 (euchromatic histone-lysine N-methyltransferase 2), is a histone methyltransferase predominantly responsible for dimethylation of histone H3 lysine 9 (H3K9). G9a has been shown to play a key role in promoting tumor progression. Recent studies have identified that G9a is a critical mediator of HCC pathogenesis. UNC0646 is a G9a inhibitor that has shown potent in vitro efficacy. However, due to its water insolubility, the in vivo efficacy of UNC0646 is not satisfactory. In this study, nanodiamonds (NDs) were utilized as a drug delivery platform to improve in vivo delivery of this small-molecule inhibitor. Our results showed that ND-UNC0646 complexes could be rapidly synthesized by physical adsorption, meanwhile possessing favorable drug delivery properties and was able to improve the dispersibility of UNC0646 in water, therefore making it amenable for intravenous administration. The release profile of UNC0646 from ND-UNC0646 was demonstrated to be pH-responsive. Moreover, ND-UNC0646 maintained the biological functionality of UNC0646, with higher efficacy in reducing H3K9 methylation as well as enhanced invasion suppressive effects. Most importantly, increased in vivo efficacy was demonstrated using an orthotopic HCC mouse model, which paves the way of translating this small-molecule inhibitor toward HCC treatment. Our work demonstrates the potential of NDs in the clinical application for HCC treatment.
Small interfering RNA (siRNA) can cause specific gene silencing and is considered promising for treating a variety of cancers, including hepatocellular carcinoma (HCC). However, siRNA has many ...undesirable physicochemical properties that limit its application. Additionally, conventional methods for delivering siRNA are limited in their ability to penetrate solid tumors. In this study, nanodiamonds (NDs) were evaluated as a nanoparticle drug delivery platform for improved siRNA delivery into tumor cells. Our results demonstrated that ND-siRNA complexes could effectively be formed through electrostatic interactions. The ND-siRNA complexes allowed for efficient cellular uptake and endosomal escape that protects siRNA from degradation. Moreover, ND delivery of siRNA was more effective at penetrating tumor spheroids compared to liposomal formulations. This enhanced penetration capacity makes NDs ideal vehicles to deliver siRNA against solid tumor masses as efficient gene knockdown and decreased tumor cell proliferation were observed in tumor spheroids. Evaluation of ND-siRNA complexes within the context of a 3D cancer disease model demonstrates the potential of NDs as a promising gene delivery platform against solid tumors, such as HCC.
Comprehensive analysis of hepatocellular carcinoma 3D models revealed enhanced penetrative siRNA delivery by a nanodiamonds compared to liposomes. Nanodiamonds were able to improve siRNA's gene knockdown and anti-cancer effects in 3D tumor models.
This data article presents datasets associated with the research article entitled “Generation of matched patient-derived xenograft in vitro–in vivo models using 3D macroporous hydrogels for the study ...of liver cancer” (Fong et al., 2018) 1. A three-dimensional macroporous sponge system was used to generate in vitro counterparts to various hepatocellular carcinoma patient-derived xenograft (HCC-PDX) lines. This article describes the viability, proliferative capacity and molecular features (genomic and transcriptomic profiles) of the cultured HCC-PDX cells. The sequencing datasets are made publicly available to enable critical or further analyzes.
A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action PtIV prodrugs. The dual targeting was established by liposomal encapsulation of ...PtIV complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of the drug‐loaded liposomes in the tumor. After the release of the PtIV prodrug inside cancer cells, a second stage of targeting directed a portion of the PtIV prodrugs to the mitochondria. Upon intracellular reduction, these PtIV prodrugs released two bioactive molecules, acting both on the mitochondrial and on the nuclear DNA. Our PtIV system showed excellent activity in vitro and in vivo, characterized by a cytotoxicity in a low micromolar range and complete tumor remission, respectively. Notably, marked in vivo activity was accompanied by reduced kidney toxicity, highlighting the unique therapeutic potential of our novel dual‐targeting dual‐action platform.
Twice as nice: A novel strategy was developed for targeted delivery of dual‐action PtIV prodrugs into cancer cells through simultaneous tumor‐ and mitochondria‐targeting. The novel highly active and nontoxic system demonstrates unique therapeutic potential for cancer treatment.
Some oncogenes encode transcription factors, but few drugs have been successfully developed to block their activity specifically in cancer cells. The transcription factor SALL4 is aberrantly ...expressed in solid tumor and leukemia cells. We developed a screen to identify compounds that reduce the viability of liver cancer cells that express high levels of SALL4, and we investigated their mechanisms.
We developed a stringent high-throughput screening platform comprising unmodified SNU-387 and SNU-398 liver cancer cell lines and SNU-387 cell lines engineered to express low and high levels of SALL4. We screened 1597 pharmacologically active small molecules and 21,575 natural product extracts from plant, bacteria, and fungal sources for those that selectively reduce the viability of cells with high levels of SALL4 (SALL4hi cells). We compared gene expression patterns of SALL4hi cells vs SALL4-knockdown cells using RNA sequencing and real-time polymerase chain reaction analyses. Xenograft tumors were grown in NOD/SCID gamma mice from SALL4hi SNU-398 or HCC26.1 cells or from SALL4lo patient-derived xenograft (PDX) cells; mice were given injections of identified compounds or sorafenib, and the effects on tumor growth were measured.
Our screening identified 1 small molecule (PI-103) and 4 natural compound analogues (oligomycin, efrapeptin, antimycin, and leucinostatin) that selectively reduced viability of SALL4hi cells. We performed validation studies, and 4 of these compounds were found to inhibit oxidative phosphorylation. The adenosine triphosphate (ATP) synthase inhibitor oligomycin reduced the viability of SALL4hi hepatocellular carcinoma and non–small-cell lung cancer cell lines with minimal effects on SALL4lo cells. Oligomycin also reduced the growth of xenograft tumors grown from SALL4hi SNU-398 or HCC26.1 cells to a greater extent than sorafenib, but oligomycin had little effect on tumors grown from SALL4lo PDX cells. Oligomycin was not toxic to mice. Analyses of chromatin immunoprecipitation sequencing data showed that SALL4 binds approximately 50% of mitochondrial genes, including many oxidative phosphorylation genes, to activate their transcription. In comparing SALL4hi and SALL4-knockdown cells, we found SALL4 to increase oxidative phosphorylation, oxygen consumption rate, mitochondrial membrane potential, and use of oxidative phosphorylation–related metabolites to generate ATP.
In a screening for compounds that reduce the viability of cells that express high levels of the transcription factor SALL4, we identified inhibitors of oxidative phosphorylation, which slowed the growth of xenograft tumors from SALL4hi cells in mice. SALL4 activates the transcription of genes that regulate oxidative phosphorylation to increase oxygen consumption, mitochondrial membrane potential, and ATP generation in cancer cells. Inhibitors of oxidative phosphorylation might be used for the treatment of liver tumors with high levels of SALL4.
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Precise control of cellular signaling events during programmed cell death is crucial yet challenging for cancer therapy. The modulation of signal transduction in cancer cells holds promise but is ...limited by the lack of efficient, biocompatible, and spatiotemporally controllable approaches. Here we report a photodynamic strategy that modulates both apoptotic and pyroptotic cell death by altering caspase-3 protein activity and the associated signaling crosstalk. This strategy employs a mitochondria-targeting, near-infrared activatable probe (termed M-TOP) that functions via a type-I photochemical mechanism. M-TOP is less dependent on oxygen and more effective in treating drug-resistant cancer cells, even under hypoxic conditions. Our study shows that higher doses of M-TOP induce pyroptotic cell death via the caspase-3/gasdermin-E pathway, whereas lower doses lead to apoptosis. This photodynamic method is effective across diverse gasdermin-E-expressing cancer cells. Moreover, the M-TOP mediated shift from apoptotic to pyroptotic modulation can evoke a controlled inflammatory response, leading to a robust yet balanced immune reaction. This effectively inhibits both distal tumor growth and postsurgical tumor recurrence. This work demonstrates the feasibility of modulating intracellular signaling through the rational design of photodynamic anticancer drugs.
To develop and validate the English version of the Satisfaction Questionnaire for Osteoporosis Prevention (SQOP) in Malaysia.
The SQOP was modified from the Osteoporosis Patient Satisfaction ...Questionnaire and developed based on literature review and patient interviews. Face and content validity were established via an expert panel. The SQOP consists of two sections: clinical services and types of counseling. There were 23 items in total, each with a five-point Likert-type response. Satisfaction score was calculated by converting the total score to a percentage. A higher score indicates higher satisfaction. English speaking, non-osteoporotic, postmenopausal women aged ≥50 years were included in the study. Participants were randomized to either the control or intervention group. Intervention participants were provided counseling, whereas control participants received none. Participants answered the SQOP at baseline and 2 weeks later.
A total of 140 participants were recruited (control group: n=70; intervention group: n=70). No significant differences were found in any demographic aspects. Exploratory factor analysis extracted seven domains. Cronbach's α for the domains ranged from 0.531-0.812. All 23 items were highly correlated using Spearman's correlation coefficient 0.469-0.996 (P<0.05), with no significant change in the control group's overall test-retest scores, indicating that the SQOP achieved stable reliability. The intervention group had a higher score than the control group (87.91±5.99 versus 61.87±8.76; P<0.05), indicating that they were more satisfied than control participants. Flesch reading ease was 62.9.
The SQOP was found to be a valid and reliable instrument for assessing patients' satisfaction towards an osteoporosis screening and prevention service in Malaysia.
Dysregulated adenosine-to-inosine (A-to-I) RNA editing is implicated in various cancers. However, no available RNA editing inhibitors have so far been developed to inhibit cancer-associated RNA ...editing events. Here, we decipher the RNA secondary structure of antizyme inhibitor 1 (AZIN1), one of the best-studied A-to-I editing targets in cancer, by locating its editing site complementary sequence (ECS) at the 3′ end of exon 12. Chemically modified antisense oligonucleotides (ASOs) that target the editing region of AZIN1 caused a substantial exon 11 skipping, whereas ECS-targeting ASOs effectively abolished AZIN1 editing without affecting splicing and translation. We demonstrate that complete 2′-O-methyl (2′-O-Me) sugar ring modification in combination with partial phosphorothioate (PS) backbone modification may be an optimal chemistry for editing inhibition. ASO3.2, which targets the ECS, specifically inhibits cancer cell viability in vitro and tumor incidence and growth in xenograft models. Our results demonstrate that this AZIN1-targeting, ASO-based therapeutics may be applicable to a wide range of tumor types.
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This work identifies an optimal chemistry for RNA editing inhibition and recognizes the importance of understanding the RNA secondary structure of cancer-associated editing substrates prior to the development of ASO-based RNA editing inhibitors. This oligonucleotide-based antisense therapy may hold great promise for the treatment of cancer.
Abstract Contrast agent-enhanced magnetic resonance (MR) imaging is critical for the diagnosis and monitoring of a number of diseases, including cancer. Certain clinical applications, including the ...detection of liver tumors, rely on both T1 and T2-weighted images even though contrast agent-enhanced MR imaging is not always reliable. Thus, there is a need for improved dual mode contrast agents with enhanced sensitivity. We report the development of a nanodiamond-manganese dual mode contrast agent that enhanced both T1 and T2-weighted MR imaging. Conjugation of manganese to nanodiamonds resulted in improved longitudinal and transverse relaxivity efficacy over unmodified MnCl2 as well as clinical contrast agents. Following intravenous administration, nanodiamond-manganese complexes outperformed current clinical contrast agents in an orthotopic liver cancer mouse model while also reducing blood serum concentration of toxic free Mn2+ ions. Thus, nanodiamond-manganese complexes may serve as more effective dual mode MRI contrast agent, particularly in cancer.