Drug-resistant Cancer Cells Research Articles

Epigallocatechin Gallate Derivative Y6 Reverses Oxaliplatin Resistance in Hepatocellular Carcinoma via Targeting the MiR-338-3p/HIF-1α/TWIST Axis to Inhibit EMT.

The emergence of drug resistance to oxaliplatin (OXA) is one of the critical obstacles in the therapy of advanced Hepatocellular Carcinoma (HCC). As an ethyl derivative of the natural compound epigallocatechin gallate (epigallocatechin-3-gallate, EGCG), Y6 was found to be able to enhance the sensitivity of HCC cells to doxorubicin. This study aimed to investigate the effect of Y6 on oxaliplatin resistance in HCC. MTT was used to determine the reversal effect of Y6 on OXA resistance. To further explore the reversal mechanism, we treated OXA alone or in combination with Y6 or EGCG in drugresistant cells and observed the morphological changes of the cells. At the same time, transwell assay was used to detect the invasion and migration ability of cells. Moreover, Real-time PCR and Western blot analysis were performed to determine the expression levels of the miR-338-3p gene, HIF-1α/Twist proteins, and EMT-related proteins. We found that Y6 could inhibit the proliferation of HCC cells and effectively reverse the drug resistance of oxaliplatin-resistant human liver cancer cells (SMMC-7721/OXA) to OXA, and the reversal effect was more significant than that of its lead drug EGCG. Most of the cells in the control group and OXA group showed typical mesenchymal-like cell morphology, while most of the cells in co-administration groups showed typical epithelioid cell morphology, and the ability of the cells to invade and migrate decreased dramatically, particularly in Y6 plus OXA group. At the same time, Y6 could up-regulate the EMT epithelial marker protein E-cadherin and down-regulate the interstitial marker protein Vimentin. In addition, in co-administration groups, the expression of miR-338-3p was up-regulated, while the expression of HIF-1α and Twist was down-regulated. Y6 significantly enhanced the susceptibility of drug-resistant cells to OXA, and the process may be related to the regulation of miR-338-3p/HIF-1α / TWIST pathway to inhibit EMT. Therefore, Y6 could be considered an effective medication resistance reversal agent, which could improve the therapeutic effect for hepatocellular cancer patients.

Polyunsaturated Fatty Acids in Quinoa Induce Ferroptosis of Colon Cancer by Suppressing Stemness.

Polyunsaturated fatty acids (PUFAs) are essential nutrients for the human body, playing crucial roles in reducing blood lipids, anti-inflammatory responses, and anticancer effect. Quinoa is a nutritionally sound food source, rich in PUFAs. This study investigates the role of quinoa polyunsaturated fatty acids (QPAs) on quelling drug resistance in colorectal cancer. The results reveal that QPA downregulates the expression of drug-resistant proteins P-gp, MRP1, and BCRP, thereby enhancing the sensitivity of colorectal cancer drug-resistant cells to the chemotherapy drug. QPA also inhibits the stemness of drug-resistant colorectal cancer cells by reducing the expression of the stemness marker CD44. Consequently, it suppresses the downstream protein SLC7A11 and leads to ferroptosis. Additionally, QPA makes the expression of ferritin lower and increases the concentration of free iron ions within cells, leading to ferroptosis. Overall, QPA has the dual-function reversing drug resistance in colorectal cancer by simultaneously inhibiting stemness and inducing ferroptosis. This study provides a new option for chemotherapy sensitizers and establishes a theoretical foundation for the development and utilization of quinoa.

Emerging Therapeutic Strategies to Overcome Drug Resistance in Cancer Cells.

The rise of drug resistance in cancer cells presents a formidable challenge in modern oncology, necessitating the exploration of innovative therapeutic strategies. This review investigates the latest advancements in overcoming drug resistance mechanisms employed by cancer cells, focusing on emerging therapeutic modalities. The intricate molecular insights into drug resistance, including genetic mutations, efflux pumps, altered signaling pathways, and microenvironmental influences, are discussed. Furthermore, the promising avenues offered by targeted therapies, combination treatments, immunotherapies, and precision medicine approaches are highlighted. Specifically, the synergistic effects of combining traditional cytotoxic agents with molecularly targeted inhibitors to circumvent resistance pathways are examined. Additionally, the evolving landscape of immunotherapeutic interventions, including immune checkpoint inhibitors and adoptive cell therapies, is explored in terms of bolstering anti-tumor immune responses and overcoming immune evasion mechanisms. Moreover, the significance of biomarker-driven strategies for predicting and monitoring treatment responses is underscored, thereby optimizing therapeutic outcomes. For insights into the future direction of cancer treatment paradigms, the current review focused on prevailing drug resistance challenges and improving patient outcomes, through an integrative analysis of these emerging therapeutic strategies.

Proteomics Analysis of Interactions between Drug-Resistant and Drug-Sensitive Cancer Cells: Comparative Studies of Monoculture and Coculture Cell Systems.

Cell-cell interactions, which allow cells to communicate with each other through molecules in their microenvironment, are critical for the growth, health, and functions of cells. Previous studies show that drug-resistant cells can interact with drug-sensitive cells to elevate their drug resistance level, which is partially responsible for cancer recurrence. Studying protein targets and pathways involved in cell-cell communication provides essential information for fundamental cell biology studies and therapeutics of human diseases. In the current studies, we performed direct coculture and indirect coculture of drug-resistant and drug-sensitive cell lines, aiming to investigate intracellular proteins responsible for cell communication. Comparative studies were carried out using monoculture cells. Shotgun bottom-up proteomics results indicate that the P53 signaling pathway has a strong association with drug resistance mechanisms, and multiple TP53-related proteins were upregulated in both direct and indirect coculture systems. In addition, cell-cell communication pathways, including the phagosome and the HIF-signaling pathway, contribute to both direct and indirect coculture systems. Consequently, AK3 and H3-3A proteins were identified as potential targets for cell-cell interactions that are relevant to drug resistance mechanisms. We propose that the P53 signaling pathway, in which mitochondrial proteins play an important role, is responsible for inducing drug resistance through communication between drug-resistant and drug-sensitive cancer cells.

Characterization and anticancer evaluation of zirconia nanoparticles synthesized via green route using sophora flavescens roots extract

The emergence of drug resistance in cancer cells has impeded recent progress in cancer therapy, leading to the investigation of novel anticancer drugs. The fabrication of metal and ZrO2 nanoparticles is a promising path with prospective applications across diverse technological domains. The present study investigates the potential anticancer effects of ZrO2 NPs obtained from the root extract of Sophora flavescens on MCF-7 breast cancer cells. The structural and chemical features of these nanoparticles are analyzed using several techniques such as flow cytometry, SEM, TEM, FTIR, and UV–vis spectroscopy. The examination of XRD and TEM images demonstrates the significant contribution of plant root extract in enhancing the efficiency of nanoparticles, leading to the formation of nearly tetragonal crystal structures with an average size of 8 nm. The MTT experiment verifies the nanoparticles' anticancer activity, which depends on the dosage. The IC50 value of 253 μg/mL indicates the half-maximal inhibitory concentration. The optical microscope reveals an unusual sight: MCF-7 cells appear more spherical and less dense at higher concentrations. This research also investigates the antibacterial properties of ZrO2 nanoparticles against harmful bacteria, particularly those resistant to multiple drugs. The diffusion disk assay indicates that the nanoparticles are active against drug-resistant isolates, with zones of inhibition ranging from 31 to 55 millimeters. Additionally, the researchers noted a positive correlation between nanoparticle concentration and the size of the inhibition zone. Overall, the data indicates the potential of ZrO2 NPs to aid in cancer therapy as well as in combating infections.

Fangchinoline targets human renal cell carcinoma cells through modulation of apoptotic and non‑apoptotic cell deaths

The process of apoptosis is one of the essential processes involved in maintenance of homeostasis in the human body. It can aid to remove misfolded proteins or cellular organelles. This sequence is especially necessary in cancer cells. However, specifically targeting already apoptotic pathways can induce drug resistance in cancer cells and hence drugs can induce cell death by alternative mechanism. We investigated whether fangchinoline (FCN) can target renal carcinoma cells by inducing multiple cell death mechanisms. Both paraptosis, autophagy, and apoptosis were induced by FCN through stimulation of diverse molecular signaling pathways. FCN induced ROS production with GSH/GSSG imbalance, and ER stress. In addition, formation of autophagosome and autophagy related markers were stimulated by FCN. Moreover, FCN induced cell cycle arrest and PARP cleavage. Except for blocking protein synthesis, these three cell death pathways were found to be complementarily working together with each other. FCN also exhibited synergistic effects with paclitaxel in inducing programmed cell death in RCC cells. Our data indicates that FCN could induce apoptotic cell death and non-apoptotic cell death pathways and can be con-tribute to development of novel cancer prevention or therapy.

Targeted delivery of FAK siRNA by engineered exosomes to reverse cetuximab resistance via activating paraptosis in colon cancer.

Cetuximab is extensively used in the treatment of metastatic colorectal cancer (mCRC). However, resistance poses a significant challenge to successful therapy. Recently, paraptosis, a non-classical programmed cell death, has garnered increased attention for its potential application value in antitumor treatments. We aimed to identify the essential pathways and signaling molecules involved in paraptosis inhibition and select them as therapeutic targets in cetuximab resistance. Additionally, engineered exosome technology is used as a drug delivery system with both targeted and effector properties. By comparing the differential expression of paraptosis-related genes between drug-resistant colon cancer cells and sensitive cells, it was observed that the paraptosis level induced by cetuximab was significantly downregulated in drug-resistant cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified the focal adhesion kinase (FAK) signaling pathway as a key pathway involved in the suppression of paraptosis. The biological function of FAK in cetuximab-resistant cells was investigated through cell morphology observation, CCK-8 assay, colony formation assay, RT-qPCR, Western Blot, and loss-of-function experiments. The results showed that the FAK signaling pathway was significantly upregulated in cetuximab-resistant colon cancer cells, and siRNA interference targeting FAK could notably inhibit cell proliferation while upregulating the paraptosis level. Based on this, engineered colon cancer cells targeted and FAK siRNA loaded exosomes (CT-Exo-siFAK1) were constructed. In vitro experiments, CT-Exo-siFAK1 could effectively activate paraptosis and inhibit the proliferation of drug-resistant colon cancer cells. In vivo experiments also confirmed that CT-Exo-siFAK1 significantly suppressed tumor growth and metastasis while upregulating the paraptosis level. This study suggests that FAK signaling pathway-mediated inhibition of paraptosis levels is crucial in the sensitivity of cetuximab targeted therapy in colon cancer, and the use of engineered exosomes to deliver FAK siRNA may be an effective strategy to reverse cetuximab resistance.

Self-assembling peptides induced by eyes absent enzyme to boost the efficacy of doxorubicin therapy in drug-resistant breast cancer cells

Enzyme-induced self-assembly (EISA) is a recently developed nanotechnology technique in which small molecules are induced by cellular enzymes self-assembling into nanostructures inside cancer cells. This technique can boost the efficacy of chemotherapy drugs by avoiding drug efflux, inhibiting the cells’ DNA repair mechanisms, and targeting the mitochondria. In this work, we study the self-assembly of a short peptide and its fluorescence analogue induced by Eyes absent (EYA) tyrosine phosphatases to boost the efficacy of doxorubicin (DOX) therapy in drug-resistant types of breast cancer cells, MDA-MB-231 and MCF-7. The peptides Fmoc–FF–YP and NBD–FF–YP were synthesized with the solid-phase peptide synthesis (SPPS) method and analyzed with HPLC and MALDI-TOF. Dynamic light scattering was used to determine the size distribution of peptides exposed to the EYA enzyme in vitro. The presence of EYA enzymes in breast cancer cells was confirmed using the western blotting assay. The intracellular location of the peptide self-assembly was studied by imaging fluorescence NBD-tagged peptides. The efficacy of the peptide alone and with DOX was determined against MCF-7 and MDA-MB-231 using MTT and LIVE-DEAD assays. Nucleus and cytoplasm F-actin (Phalloidin) staining was used to determine cell morphology changes in response to the combination therapy of peptides/DOX. At an optimal concentration, the peptides are not toxic to the cells; however, they boost the efficacy of DOX against drug-resistant breast cancer cells. We used state-of-the-art computer-aided techniques to predict the molecular structure of peptides and their interactions with EYA. This study demonstrates an approach for incorporating non-cytotoxic components into DOX combination therapy, thereby avoiding increased systemic burden or adverse effects.

Dynamic analysis of a drug resistance evolution model with nonlinear immune response

Recent studies have utilized evolutionary mechanisms to impede the emergence of drug-resistant populations. In this paper, we develop a mathematical model that integrates hormonal treatment, immunotherapy, and the interactions among three cell types: drug-sensitive cancer cells, drug-resistant cancer cells and immune effector cells. Dynamical analysis is performed, examining the existence and stability of equilibria, thereby confirming the model’s interpretability. Model parameters are calibrated using available prostate cancer data and literature. Through bifurcation analysis for drug sensitivity under different immune effector cells recruitment responses, we find that resistant cancer cells grow rapidly under weak recruitment response, maintain at a low level under strong recruitment response, and both may occur under moderate recruitment response. To quantify the competitiveness of sensitive and resistant cells, we introduce the comprehensive measures R1 and R2, respectively, which determine the outcome of competition. Additionally, we introduce the quantitative indicators CIE1 and CIE2 as comprehensive measures of the immune effects on sensitive and resistant cancer cells, respectively. These two indicators determine whether the corresponding cancer cells can maintain at a low level. Our work shows that the immune system is an important factor affecting the evolution of drug resistance and provides insights into how to enhance immune response to control resistance.

ATTAINMENT: A phase Ib trial of MDX-124, a first-in-class annexin-A1 targeting antibody, alone and in combination with anti-cancer treatments, in patients with advanced solid tumors.

TPS2671 Background: Annexin-A1 is a Ca2+-dependent phospholipid binding protein that is secreted from both cancer and immune cells in response to several physiological stimuli. Secreted annexin-A1 activates formyl peptide receptors driving cancer cell proliferation, angiogenesis, migration, and drug resistance, as well as modulating the tumor microenvironment. Annexin-A1 overexpression is observed in multiple cancers, including pancreatic, triple-negative breast, colorectal, lung and prostate, correlating with poor prognosis and decreased overall survival. MDX-124 is a novel, first-in-class humanised monoclonal antibody that targets annexin-A1. It significantly reduces cancer cell growth via cell cycle arrest, inhibits tumour growth in-vivo, reduces metastasis and induces antibody-dependent cellular cytotoxicity in annexin-A1 expressing cancer cells. Additionally, MDX-124 has synergistic activity when combined with chemotherapy and immunotherapy in pre-clinical models. These data indicate blocking the action of annexin-A1 has anti-cancer and therapeutic activity. Methods: ATTAINMENT is a modular, multi-arm, First-in-Human trial to evaluate the safety and tolerability of MDX-124 alone and in combination with anti-cancer treatments, in participants with locally advanced, unresectable, or metastatic solid malignancies. Module 1 is a single agent dose escalation using a Bayesian optimal interval (BOIN) design with an expansion cohort, followed by Module 2, which will evaluate MDX-124 in combination with standard of care in indication-specific arms by using a traditional 3+3 dose escalation scheme. Adult patients (≥18 years) with ECOG performance score 0-1 and histologically/cytologically confirmed solid tumors believed to overexpress annexin-A1 which are not amenable to or refractory to standard therapy, or for which no standard therapy exists are eligible. The primary objective is to determine the recommended phase 2 dose (RP2D) of MDX-124 both as a single agent and in combination with anti-cancer treatments. Secondary objectives will assess the safety and tolerability of MDX-124 when given as a single agent or in combination with anti-cancer treatments, characterize pharmacokinetic parameters and assess evidence of preliminary anti-tumor activity per RECIST v1.1 criteria. Exploratory objectives will assess host immune response to MDX-124 (immunogenicity and immunophenotyping), circulating levels of annexin-A1 at baseline and after dosing to correlate with response and outcome to MDX-124, and the impact of MDX-124 on blood/tissue biomarkers. The study began enrolling patients at sites in the UK in August 2023. Cohorts at 1, 2.5 and 5 mg/kg have been completed without DLT and enrollment to cohort 4 (10 mg/kg) began in January 2024. Clinical trial information: ISRCTN78740398.

Caffeic Acid Enhances Anticancer Drug-induced Apoptosis in Acid-adapted HCT116 Colon Cancer Cells.

Apoptosis resistance in cancer cells adapted to acidic microenvironments poses a challenge for effective treatment. This study investigated the potential use of caffeic acid as an adjunct therapy to overcome drug resistance in colorectal cancer cells under acidic conditions. Long-term exposure to low-pH conditions induced resistance in HCT116 colorectal cancer cells. The effects of caffeic acid on proliferation, clonogenicity, and apoptosis induction were assessed alone and in combination with oxaliplatin and 5-Fluorouracil. The signaling pathways involved in drug resistance were examined by assessing the activities of PI3K/Akt and ERK1/2. Caffeic acid inhibited the proliferation and clonogenicity of acid-adapted cancer cells, and enhanced apoptosis when combined with anticancer drugs. Mechanistically, caffeic acid attenuated the hyperactivation of the PI3K/Akt and ERK1/2 signaling pathways associated with drug resistance. Caffeic acid is a promising therapeutic agent for targeting resistant cancer cells in acidic microenvironments. Its ability to inhibit proliferation, sensitize cells to apoptosis, and modulate signaling pathways highlights its potential for overcoming drug resistance in cancer therapy.

The novel SMYD3 inhibitor EM127 impairs DNA repair response to chemotherapy-induced DNA damage and reverses cancer chemoresistance

BackgroundSMYD3 has been found implicated in cancer progression. Its overexpression correlates with cancer growth and invasion, especially in gastrointestinal tumors. SMYD3 transactivates multiple oncogenic mechanisms, favoring cancer development. Moreover, it was recently shown that SMYD3 is required for DNA restoration by promoting homologous recombination (HR) repair.MethodsIn cellulo and in vivo models were employed to investigate the role of SMYD3 in cancer chemoresistance. Analyses of SMYD3-KO cells, drug-resistant cancer cell lines, patients’ residual gastric or rectal tumors that were resected after neoadjuvant therapy and mice models were performed. In addition, the novel SMYD3 covalent inhibitor EM127 was used to evaluate the impact of manipulating SMYD3 activity on the sensitization of cancer cell lines, tumorspheres and cancer murine models to chemotherapeutics (CHTs).ResultsHere we report that SMYD3 mediates cancer cell sensitivity to CHTs. Indeed, cancer cells lacking SMYD3 functions showed increased responsiveness to CHTs, while restoring its expression promoted chemoresistance. Specifically, SMYD3 is essential for the repair of CHT-induced double-strand breaks as it methylates the upstream sensor ATM and allows HR cascade propagation through CHK2 and p53 phosphorylation, thereby promoting cancer cell survival. SMYD3 inhibition with the novel compound EM127 showed a synergistic effect with CHTs in colorectal, gastric, and breast cancer cells, tumorspheres, and preclinical colorectal cancer models.ConclusionsOverall, our results show that targeting SMYD3 may be an effective therapeutic strategy to overcome chemoresistance.

Necroptosis induced by ruthenium (II) complexes as mitochondrial disruptors

Inducing necroptosis in cancer cells has emerged as an effective strategy to overcome drug resistance. However, while organic small molecules have been extensively studied for this purpose, metal-based compounds have received relatively little attention as triggers of necroptosis. The development of ruthenium (II) hybrid compounds, particularly those containing triazene (Ru-TRZ), highlights a novel avenue for modulating necroptotic cell death. Here we show that incorporating a methyltriazene moiety, a known alkylating warhead, confers superior mitochondrial-targeting properties and enhances cell death compared to amide-containing counterparts. Ru-hybrid TRZ2 exhibits also antitumor efficacy against in vivo drug-resistant cancer cells. Mechanistically, we demonstrate that Ru-TRZ hybrids induce apoptosis. In addition, by activating downstream RIPK3-driven cell death, TRZ2 proficiently restrains normal mitochondrial function and activity, leading to cancer cell necroptosis. Finally, TRZ2 synergizes anti-proliferative activity and cell death effects induced by conventional drugs. In conclusion, Ru-TRZ2 stands as a promising ruthenium-based chemotherapeutic agent inducing necroptosis in drug resistant cancer cells.

KDM5B promotes SMAD4 loss-driven drug resistance through activating DLG1/YAP to induce lipid accumulation in pancreatic ductal adenocarcinoma

Inactivated suppressor of mothers against decapentaplegic homolog (SMAD) 4 significantly affects cancer development in pancreatic ductal adenocarcinoma (PDAC). However, the contribution of smad4 loss to drug resistance in PDAC is largely undetermined. In the present study, we reported that the loss of SMAD4 endows PDAC cells the ability to drug resistance through upregulating histone lysine demethylase, Lysine-Specific Demethylase 5B (KDM5B, also known as JARID1B or PLU1). Upregulated KDM5B was found in PDAC, associated with poor prognosis and recurrence of PDAC patients. Upregulated KDM5B promotes PDAC tumor malignancy, i.e. cancer cells stemness and drug resistance in vitro and in vivo, while KDM5B knockout exerts opposite effects. Mechanistically, loss of Smad4-mediated upregulation of KDM5B promotes drug resistance through inhibiting the discs-large homolog 1 (DLG1), thereby facilitating nuclear translocation of YAP to induce de novo lipogenesis. Moreover, m6A demethylase FTO is involved in the upregulation of KDM5B by maintaining KDM5B mRNA stability. Collectively, the present study suggested FTO-mediated KDM5B stabilization in the context of loss of Smad4 activate DLG1/YAP1 pathway to promote tumorigenesis by reprogramming lipid accumulation in PDAC. Our study confirmed that the KDM5B-DLG1-YAP1 pathway axis plays a crucial role in the genesis and progression of PDAC, and KDM5B was expected to become a target for the treatment of PDAC.The schematic diagram of KDM5B-DLG1-YAP pathway axis in regulating drug resistance of PDAC to gemcitabine (GEM). In the context of SMAD4 loss PDAC cells, FTO-mediated stabilization and upregulation of KDM5B promotes drug resistance through directly targeting DLG1 to promote YAP1 translocation to nucleus to induce de novo lipogenesis (DNL).

Synthesis and new DNA targeting activity of 6- and 7-tert-butylfascaplysins

Fascaplysin is a red cytotoxic pigment with anticancer properties isolated from the marine sponge Fascaplysinopsis sp. Recently, structure–activity relationship analysis reported by our group suggested that selective cytotoxicity of fascaplysin derivatives towards tumor cells negatively correlates with their ability to intercalate into DNA. To validate this hypothesis, we synthesized 6- and 7-tert-butylfascaplysins which reveal mitigated DNA-intercalating properties. These derivatives were found to be strongly cytotoxic to drug-resistant human prostate cancer cells, albeit did not demonstrate improved selectivity towards cancer cells when compared to fascaplysin. At the same time, kinome analysis suggested an activation of CHK1/ATR axis in cancer cells shortly after the drug exposure. Further experiments revealed induction of replication stress that is eventually converted to the toxic DNA double-strand breaks, resulting in caspase-independent apoptosis-like cell death. Our observations highlight new DNA-targeting effect of some fascaplysin derivatives and indicate more complex structure–activity relationships within the fascaplysin family, suggesting that cytotoxicity and selectivity of these alkaloids are influenced by multiple factors. Furthermore, combination with clinically-approved inhibitors of ATR/CHK1 as well as testing in tumors particularly sensitive to the DNA damage should be considered in further studies.

Harnessing endocytic pH gradients for cascaded formation of intracellular condensates to inhibit autophagy: A pathway to cancer therapy

Cancer cells rely on autophagy to degrade damaged organelles and survive in the harsh environment for progression and metastasis. Autophagy inhibition can improve the efficacy of anticancer therapy because many anticancer drugs can induce protective autophagy in cancer cells. However, current clinically available autophagy inhibitors are rare and have adverse effects with limited selectivity. This work develops an intracellular biomolecular condensate for autophagy inhibition to kill cancer without apparent side effects. A modularly designed amphiphilic peptide (PNP) can self-assemble to form toxic nanofibrous condensates successively from nanoparticles with the pH changes of the endocytic pathway. Mechanistic studies by CLSM and FRAP demonstrate that the PNP finally forms solid nanofibrous condensates in the lysosome after cell endocytosis. Bio-EM and cell transfection with adenovirus expressing mCherry-GFP-LC3B fusion protein (autophagy marker) experiments indicate the autophagy inhibition by PNP nanofibrous condensates. In vitro experiments show that PNP can significantly boost the activity of the clinical drug by 150-fold against drug-resistant lung cancer cells by inducing G2/M phase arrest of the cell cycle. Furthermore, PNPs demonstrate effective tumor targeting and permeability in vivo, inhibiting tumor growth and reducing the side effects of clinical chemotherapy drugs. Overall, this work provides a simple and feasible strategy for designing intracellular condensates to inhibit autophagy for cancer therapy.

LncRNA TUG1 and its Molecular Mechanisms in Human Cancer.

As lncRNAs have increasingly been investigated, they are no longer simply defined as RNAs with no transcription capability. Studies have identified significant associations between the abnormal expression of lncRNAs and human diseases, particularly the mechanisms by which lncRNAs play a part in cancers, which are of considerable attention to researchers. As a result of the complex spatial structure, the mechanisms of interaction of lncRNAs in cancer cells are also complicated and diversified. Among a series of lncRNAs, TUG1, which is now considered to be a very high-value lncRNA, has recently been identified to express abnormally in some malignancies, leading to different alterations in cancer cells proliferation, migration, invasion, apoptosis, and drug resistance, and hence promoting or inhibiting cancer progression. Current studies have implicitly indicated that TUG1 can be used as a therapeutic target for human cancers. However, the biological functions of TUG1 have been studied for a short period of time, and the complete molecular mechanism still needs to be clarified. Accordingly, this review focuses on the principal molecular mechanisms of TUG1 in human cancers and the specific mechanisms of action in different cancer development processes based on existing studies.

The new seriniquinone glycoside by biological transformation using the deep sea-derived bacterium Bacillus licheniformis KDM612

Seriniquinone was isolated as a melanoma-selective anti-cancer agent from a culture broth of the marine-derived bacterium Serinicoccus marinus CNJ927 in 2014. It targets the unique small protein, dermcidin, which affects the drug resistance of cancer cells. Due to its significant activity against cancer cells, particularly melanoma, and its unique target, seriniquinone has been developed as a new pharmacophore. However, it has the disadvantage of poor solubility in drug discovery research, which needs to be resolved. A new seriniquinone glycoside (1) was synthesized by the biological transformation of seriniquinone using the deep sea-derived bacterium Bacillus licheniformis KDM612. Compound 1 exhibited selective anti-cancer activity against melanoma, similar to seriniquinone, and was 50-fold more soluble in DMSO than seriniquinone.

Dissimilar effect of organometallic ruthenium complexes on the viability of MDR and non-MDR experimental models

Ruthenium complexes containing triphenylphosphine diamide ligands were prepared, characterized, and tested for their biological activity against various cancer cell lines and the malaria parasite, Plasmodium falciparum. The effect of M (mono-substituted) and B (bis-substituted) complexes on the human cervical carcinoma (HeLa) cell line was investigated using the MTT assay. Five (B2, B3, B5, B6, and B13) of the 24 synthesized ruthenium complexes showed significant effects with IC50 values ranging between 0.3 and 2.3 μM. Evaluation of the potential biomolecular targets of B2 and B13 by fluorescence spectroscopy revealed relevant interactions with BSA and only a weak affinity for ctDNA. Complexes M2, B2, M13 and B13 were selected for further biological characterization. Their effect on the viability of two ovarian cancer cell lines was compared to normal cell lines, denoting their selectivity. Upon treatment of four different drug-resistant gynaecological cancer cell lines, differing in their multidrug-resistant phenotypes, the efficacy of the bis-substituted complexes was shown to be greater than their mono-substituted counterparts. The non-MDR cells are sensitive to all the tested complexes, compared to MDR cells which are less sensitive. Upon investigation of complexes M2, M13, B2, and B13 against sensitive and multidrug-resistant parasite strains of P. falciparum, the bis-substituted complexes were again shown to be the most potent, with submicromolar activity against both strains. Furthermore, the resistance indexes for the complexes were approximately equal to 1, which is at least 5-fold lower than chloroquine diphosphate, suggesting the ability of these complexes to retain their activity in resistant forms of the parasite.

Three-in-one DNA nanowheels for simultaneous tumor regression and drug resistance prevention in breast cancer model

Herein, we proposed novel three-in-one DNA nanowheels with simultaneous chemo and gene therapy to treat tumor, especially to prevent simultaneous drug resistance, which could be disassembled via a cascaded hybridization reactions triggered by the highly expressed microRNA in cancer cells for smart and efficient cancer therapy. Typically, with breast cancer as a model, microRNA 21 could trigger the self-disassembly of DNA nanowheel 1 via hybridization with a specially designed oligonucleotide (anti-microRNA 21) in DNA nanowheel 1, releasing another special oligonucleotide (Contact sequence) to trigger the self-disassembly of DNA nanowheel 2 with releasing of a special oligonucleotide (anti-Contact sequence) to trigger the self-disassembly of DNA nanowheel 1 cyclically, and thus the cascaded hybridization reactions with three-in-one anti-cancer functions could be generated based on three main therapeutic effects via releasing doxorubicin to inhibit macromolecular biosynthesis, antisense oligonucleotide of microRNA 21 to activate the apoptotic cell pathway and antisense oligonucleotide of MDR1 to prevent the drug resistance respectively. As expected, the proposed method showed improved therapeutic efficacy on the cancer cells with about 80% apoptosis ratio, especially on the drug resistant cancer cells with about 75% apoptosis ratio, compared with that in the conventional anti-cancer systems of about 70% on cancer cells and below 40% on drug resistant cancer cells, respectively. Most importantly, this strategy opened the door for generation of complex functional DNA-based structures for target triggering drugs releasing system combining with chemo- and gene-therapy to generate tumor regression and prevent drug resistance with an optimized therapeutic efficacy, providing a new avenue for efficient cancer treatment, especially drug resistant cancers.