Breast cancer is a multifaceted and prevalent malignancy, impacting a considerable proportion of women globally. Numerous signaling pathways intricately regulate cellular functions such as growth, proliferation, and survival. Among the various regulators, lncRNAs have emerged as significant players despite their inability to encode proteins. An expanding body of literature underscores the pivotal roles lncRNAs play in cancer biology, particularly in the context of breast cancer. Autophagy, the cellular process dedicated to the degradation and recycling of cellular components, is now recognized as a crucial factor in cancer initiation and progression. The interplay between lncRNAs, various signaling pathways, and autophagy in the pathophysiology of breast cancer remains an active area of investigation. Researchers have identified specific lncRNAs that are dysregulated in breast cancer patients, influencing the modulation of key signaling pathways. Using experimental methodologies and bioinformatics approaches, multiple lncRNAs have been elucidated, providing deeper insights into their contributions to breast cancer pathogenesis and metastatic processes. In summary, the pathophysiological landscape of breast cancer is characterized by the complex interactions involving lncRNA-mediated autophagy. This understanding paves the way for identifying novel therapeutic targets, prognostic markers, and diagnostic markers, ultimately contributing to improved treatment outcomes in breast cancer management.

Lung cancer is one of the most prevalent malignancies globally and is the leading cause of cancer-related mortality. Although cisplatin is a widely utilized chemotherapeutic agent, its clinical efficacy is often hampered by significant toxicity and undesirable side effects. Rosa canina, a medicinal plant, has demonstrated a range of beneficial biological activities, including anti-inflammatory, anticancer, immunomodulatory, antioxidant, and genoprotective effects.

This study aimed to investigate the potential of Rosa canina to enhance the anticancer efficacy of cisplatin in a dimethyl benz(a)anthracene-induced lung cancer model using female rats. The animals were administered Rosa canina, cisplatin, or a combination of both treatments. The expression levels of critical signaling molecules were evaluated, including phosphoinositide-3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), cleaved poly (ADP-ribose) polymerase (PARP-1), myeloid differentiation factor 88 (MyD88), and tumor necrosis factor receptor-associated factor (TRAF), in addition to various autophagic markers. Furthermore, we assessed the levels of toll-like receptor 2 (TLR2), nuclear factor kappa B (NF-κB), and apoptotic markers in lung tissue, complemented by histopathological examinations.

The combined treatment of Rosa canina extract and cisplatin significantly inhibited lung cancer cell proliferation by downregulating PARP-1 and the TLR2/MyD88/TRAF6/NF-κB signaling pathway, as well as the PI3K/Akt/mTOR pathway. Moreover, this combination therapy promoted autophagy and apoptosis, evidenced by elevated levels of autophagic and apoptotic markers.

Overall, the findings of this study suggest that Rosa canina enhances the anticancer effects of cisplatin by inhibiting cancer cell proliferation while simultaneously inducing autophagy and apoptosis. Thus, Rosa can be used as adjuvant to cisplatin chemotherapy to overcome its limitations which may be considered a new approach during lung cancer treatment strategy.

Sepsis-associated encephalopathy (SAE) is common and has poor clinical outcome. Sepsis increases autophagy in the brain. This study was designed to determine the role of autophagy on SAE including the brain structures related to learning and memory and the effects of pyrrolidine dithiocarbamate (PDTC), an anti-inflammatory agent, on autophagy and SAE. Six- to eight-week old CD-1 male mice were subjected to cecal ligation and puncture (CLP). Some mice received intracerebroventricular injection of the autophagy suppressor 3-methyladenine (3-MA) or intraperitoneal injection of PDTC immediately at the completion of the CLP. ELISA was used to measure interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor α. Autophagy-related protein expression in the cerebral cortex and hippocampus was analyzed by Western blotting. The cognitive functions of mice were analyzed by Barnes maze and fear conditioning tests. CLP increased microtubuleassociated protein light chain 3 II (LC3II) and Beclin 1 and decreased p62 in the brain. CLP also increased proinflammatory cytokines and impaired learning and memory. These effects were inhibited by 3-MA and PDTC. Spine proliferation and maturation were impaired by CLP, which was attenuated by PDTC and 3MA. Abundant autophagic vacuoles were observed by transmission electron microscopy in CLP group. LC3II immunostaining was co-localized with that of ionized calcium-binding adapter molecule 1 and microtubule-associated protein-2. The co-staining was attenuated by 3-MA and PDTC. Our results suggest that sepsis increases autophagy in the microglia and neurons. Inhibiting autophagy improves SAE and brain structures related to learning and memory in mice. Autophagy and inflammation in the brain may regulate each other during sepsis.

Osteosarcoma, a highly malignant skeletal tumor, primarily affects children and adolescents. Autophagy plays a crucial role in osteosarcoma pathophysiology. This study utilizes bibliometric analysis to evaluate current research on autophagy in osteosarcoma and forecast future directions.

We conducted a comprehensive search of publications in the Web of Science Core Collection database from January 1, 2008, to March 15, 2024. Tools like VOSviewer, CiteSpace, R software, Excel, and Scimago were used for analysis and visualization.

Publications increased steadily over 17 years, indicating rising interest. Zhang Yuan was the most influential author, with Shanghai Jiao Tong University leading. Cell Death & Disease was the top journal. "HMGB1 Promotes Drug Resistance in Osteosarcoma" was the most cited paper. Co-cited articles focused on drug resistance, therapeutic targets, autophagy in cancer, and genomic impacts on immunotherapy. Keywords highlighted invasion, migration, cell death, and breast cancer as research hotspots. Future studies will likely focus on therapeutic innovations and integrated management strategies.

This bibliometric analysis offers an overview of current knowledge and emerging trends in autophagy and osteosarcoma, emphasizing key areas like invasion, migration, and cell death. It serves as a valuable resource for researchers developing novel therapies for osteosarcoma.

Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity with reasonable pharmacokinetics. Non-toxicity is demonstrated in a non-cancer cell line and in mice at doses achieving drug exposure at active concentrations. Anti-tumour properties of both chemotypes were validated in mouse xenografts against A549 human lung cancer and, for one of the chemotypes, against HT-29 colorectal cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex. Treatment with these compounds alters the target multi-protein complexes in a manner that appears to remove a block, crucial for cancer survival and progression, on a homeostatic linkage between uncontrolled proliferation and apoptosis. These compounds provide starting points for development of novel, next-generation, non-toxic, pan-cancer therapeutics.

N6 methyladenosine (m6A), methylation at the sixth N atom of adenosine, is the most common and abundant modification in mammalian mRNAs and non-coding RNAs. Increasing evidence shows that the alteration of m6A modification level could regulate tumour proliferation, metastasis, self-renewal, and immune infiltration by regulating the related expression of tumour genes. However, the role of m6A modification in colorectal cancer (CRC) drug resistance is unclear. Here, MeRIP-seq and RNA-seq techniques were utilized to obtain mRNA, lncRNA expression, and their methylation profiles in 5-Fluorouracil (5-FU)-resistant colon cancer HCT-15 cells and control cells. In addition, we performed detailed bioinformatics analysis as well as in vitro experiments of lncRNA to explore the function of lncRNA with differential m6A in CRC progression and drug resistance. In this study, we obtained the m6A methylomic landscape of CRC cells and resistance group cells by MeRIP-seq and RNA-seq. We identified 3698 differential m6A peaks, of which 2224 were hypermethylated, and 1474 were hypomethylated. Among the lncRNAs, 60 were hypermethylated, and 38 were hypomethylated. GO and KEGG analysis annotations showed significant enrichment of endocytosis and MAPK signalling pathways. Moreover, knockdown of lncRNA ADIRF-AS1 and AL139035.1 promoted CRC proliferation and invasive metastasis in vitro. lncRNA- mRNA network showed that ADIRF-AS1 and AL139035.1 May play a key role in regulating drug resistance formation. We provide the first m6A methylation profile in 5-FU resistance CRC cells and analyse the functions of differential m6A-modified mRNAs and lncRNAs. Our results indicated that differential m6A RNAs were significantly associated with MAPK signalling and endocytosis after induction of 5-FU resistance. Knockdown of LncRNA ADIRF-AS1 and AL139035.1 promotes CRC progression and might be critical in regulating drug resistance formation.

Breast cancer is a common malignancy in women, and its metastasis is a leading cause of cancer-related deaths. Single-cell RNA sequencing (scRNA-seq) can distinguish the molecular characteristics of metastasis and identify predictor genes for patient prognosis. This article explores gene expression in primary breast cancer tumor tissue against metastatic cells in the lymph node and liver using scRNA-seq.

Breast cancer scRNA-seq data from the Gene Expression Omnibus were used. The data were processed using R and the Seurat package. The cells were clustered and identified using Metascape. InferCNV is used to analyze the variation in copy number. Differential expression analysis was conducted for the cancer cells using Seurat and was enriched using Metascape.

We identified 18 distinct cell clusters, 6 of which were epithelial. CNV analysis identified significant alterations with duplication of chromosomes 1, 8, and 19. Differential gene analysis resulted in 17 upregulated and 171 downregulated genes for the primary tumor in the primary tumor vs. liver metastasis comparison and 43 upregulated and 4 downregulated genes in the primary tumor in the primary tumor vs lymph node metastasis comparison. Several enriched terms include Ribosome biogenesis, NTP synthesis, Epithelial dedifferentiation, Autophagy, and genes associated with epithelial-to-mesenchymal transitions.

No single gene or pathway can clearly explain the mechanisms behind tumor metastasis. Several mechanisms contribute to lymph node and liver metastasis, such as the loss of differentiation, epithelial-to-mesenchymal transition, and autophagy. These findings necessitate further study of metastatic tissue for effective drug development.

Groenlandicine is a protoberberine alkaloid isolated from Coptidis Rhizoma, a widely used traditional Chinese medicine known for its various biological activities. This study aims to validate groenlandicine's effect on both cisplatin-sensitive and cisplatin-resistant osteosarcoma (OS) cells, along with exploring its potential molecular mechanism. The ligand-based virtual screening (LBVS) method and molecular docking were employed to screen drugs. CCK-8 and FCM were used to measure the effect of groenlandicine on the OS cells transfected by lentivirus with over-expression or low-expression of TOP1. Cell scratch assay, CCK-8, FCM, and the EdU assay were utilized to evaluate the effect of groenlandicine on cisplatin-resistant cells. WB, immunofluorescence, and PCR were conducted to measure the levels of TOP1, Bcl-2, BAX, Caspase-9, and Caspase-3. Additionally, a subcutaneous tumor model was established in nude mice to verify the efficacy of groenlandicine. Groenlandicine reduced the migration and proliferation while promoting apoptosis in OS cells, effectively damaging them. Meanwhile, groenlandicine exhibited weak cytotoxicity in 293T cells. Combination with cisplatin enhanced tumor-killing activity, markedly activating BAX, cleaved-Caspase-3, and cleaved-Caspase-9, while inhibiting the Bcl2 pathway in cisplatin-resistant OS cells. Moreover, the level of TOP1, elevated in cisplatin-resistant OS cells, was down-regulated by groenlandicine both in vitro and in vivo. Animal experiments confirmed that groenlandicine combined with cisplatin suppressed OS growth with lower nephrotoxicity. Groenlandicine induces apoptosis and enhances the sensitivity of drug-resistant OS cells to cisplatin via the BAX/Bcl-2/Caspase-9/Caspase-3 pathway. Groenlandicine inhibits OS cells growth by down-regulating TOP1 level.Therefore, groenlandicine holds promise as a potential agent for reversing cisplatin resistance in OS treatment.

Osteosarcoma, the most prevalent primary malignant bone tumor and the third most frequent cancer in children and adolescents worldwide, still poses a significant therapeutic challenge. Even though combined chemotherapy and surgical resection have improved survival rates up to 60%, the prognosis for most patients with metastatic osteosarcoma continues to be dismal. The specific pathogenesis and key regulators of tumor invasion and metastasis remain largely elusive. Circular RNAs (circRNAs), novel endogenous non-coding RNA molecules that form covalently closed continuous loops through splicing, play a crucial role in the development, progression, clinical diagnosis, and treatment of various diseases. Recently, an escalating number of circular structures have been identified in osteosarcoma. Understanding their role in osteosarcoma is advantageous for early detection, diagnosis, and treatment of this disease. The primary function of circRNA involves its unique ability to bind specifically to miRNA, although their biological functions also extend to interacting with proteins, regulating gene transcription, and serving as translation templates. In this review, we explore the mechanisms and clinical applications of circRNAs in the pathogenesis and progression of osteosarcoma, with a particular emphasis on the regulatory mechanisms and functions of circRNAs as miRNA sponges in osteosarcoma development.

Pristimerin is a natural triterpenoid that has received much attention from medicinal chemists for its multiple biological activities. However, structural modifications of pristimerin, especially those aimed at discovering antitumor agents, are relatively limited. In this study, two series of pristimerin derivatives containing phenyloxazole and quinoxaline moieties, respectively, were designed via the scaffold hopping strategy. The target compounds were synthesized and analyzed for their cytotoxic activities in vitro using the MTT assay. The most potent cytotoxic compound (21o) significantly inhibited the proliferation of MCF-7 cells with an IC50 value of 2.0 μM, 1.5-fold more potent than pristimerin (IC50 = 3.0 μM). Compared with pristimerin, compound 21o displayed the greatest improvement in selectivity (25.7-fold) against the MCF-7 and MCF-10A cell lines. Transmission electron microscopy, monodansylcadaverine and DCFH-DA staining, Western blotting, and different inhibitor assays were performed to elucidate the mechanism of action of compound 21o. Compound 21o induced autophagy-mediated cell death in MCF-7 cells by activating the ROS/JNK signaling pathway. Therefore, incorporating a quinoxaline substructure into pristimerin could be advantageous for enhancing its cytotoxic activity. Compound 21o may serve as a lead compound for developing new therapies to treat breast cancer.

Besides producing cellular energy, mitochondria are crucial in controlling oxidative stress and modulating cellular metabolism, particularly under stressful conditions. A key aspect of this regulatory role involves the recycling process of autophagy, which helps to sustain energy homeostasis. Autophagy, a lysosome-dependent degradation pathway, plays a fundamental role in maintaining cellular homeostasis by degrading damaged organelles and misfolded proteins. In the context of tumor formation, autophagy significantly influences cancer metabolism and chemotherapy resistance, contributing to both tumor suppression and surveillance. This review focuses on the relationship between mitochondria and autophagy, specifically in the context of cancer progression. Investigating the interaction between autophagy and mitochondria reveals new possibilities for cancer treatments and may result in the development of more effective therapies targeting mitochondria, which could have significant implications for cancer treatment. Additionally, this review highlights the increasing understanding of autophagy's role in tumor development, with a focus on modulating mitochondrial function and autophagy in both pre-clinical and clinical cancer research. It also explores the potential for developing more-targeted and personalized therapies by investigating autophagy-related biomarkers.

The mechanisms enabling dynamic shifts between drug-resistant and drug-sensitive states in cancer cells are still underexplored. This study investigated the role of targeted autophagic protein degradation in regulating ovarian cancer stem cell (CSC) fate decisions and chemo-resistance.

Autophagy levels were compared between CSC-enriched side population (SP) and non-SP cells (NSP) in multiple ovarian cancer cell lines using immunoblotting, immunofluorescence, and transmission electron microscopy. The impact of autophagy modulation on CSC markers and differentiation was assessed by flow cytometry, immunoblotting and qRT-PCR. In silico modeling and co-immunoprecipitation identified ID1 interacting proteins. Pharmacological and genetic approaches along with Annexin-PI assay, ChIP assay, western blotting, qRT-PCR and ICP-MS were used to evaluate effects on cisplatin sensitivity, apoptosis, SLC31A1 expression, promoter binding, and intracellular platinum accumulation in ID1 depleted backdrop. Patient-derived tumor spheroids were analyzed for autophagy and SLC31A1 levels.

Ovarian CSCs exhibited increased basal autophagy compared to non-CSCs. Further autophagy stimulation by serum-starvation and chemical modes triggered proteolysis of the stemness regulator ID1, driving the differentiation of chemo-resistant CSCs into chemo-sensitive non-CSCs. In silico modeling predicted TCF12 as a potent ID1 interactor, which was validated by co-immunoprecipitation. ID1 depletion freed TCF12 to transactivate the cisplatin influx transporter SLC31A1, increasing intracellular cisplatin levels and cytotoxicity. Patient-derived tumor spheroids exhibited a functional association between autophagy, ID1, SLC31A1, and platinum sensitivity.

This study reveals a novel autophagy-ID1-TCF12-SLC31A1 axis where targeted autophagic degradation of ID1 enables rapid remodeling of CSCs to reverse chemo-resistance. Modulating this pathway could counter drug resistance in ovarian cancer.

Cisplatin (CDDP) is a commonly used chemotherapeutic for osteosarcoma (OS) patients, and drug resistance remains as a major hurdle to undermine the treatment outcome. Here, we investigated the potential involvement of FoxG1 and BNIP3 in CDDP resistance of OS cells. FoxG1 and BNIP3 expression levels were detected in the CDDP-sensitive and CDDP-resistant OS tumors and cell lines. Mitophagy was observed through transmission electron microscope analysis. The sensitivity to CDDP in OS cells upon FoxG1 overexpression was examined in cell and animal models. We found that FoxG1 and BNIP3 showed significant downregulation in the CDDP-resistant OS tumor samples and cell lines. CDDP-resistant OS tumor specimens and cells displayed impaired mitophagy. FoxG1 overexpression promoted BNIP3 expression, enhanced mitophagy in CDDP-resistant OS cells, and resensitized the resistant cells to CDDP treatment in vitro and in vivo. Our data highlighted the role of the FoxG1/BNIP3 axis in regulating mitophagy and dictating CDDP resistance in OS cells, suggesting targeting FoxG1/BNIP3-dependent mitophagy as a potential strategy to overcome CDDP resistance in OS.

Classical Hodgkin Lymphomas (HL) are a unique malignant growth with an excellent initial prognosis. However, 10-30% of patients will still relapse after remission. One primary cellular function that has been the focus of tumor progression is autophagy. This process can preserve cellular homeostasis under stressful conditions. Several studies have shown that autophagy may play a role in developing HL. Therefore, this review aimed to explore chemotherapy's effect on autophagy in HL, and the effects of autophagy on HL.

A scoping review in line with the published PRISMA extension for scoping reviews (PRISMA-ScR) was conducted. A literature search was conducted on the MEDLINE database and the Cochrane Central Register of Controlled Trials (CENTRAL). All results were retrieved and screened, and the resulting articles were synthesized narratively.

The results showed that some cancer chemotherapy also induces autophagic flux. Although the data on HL is limited, since the mechanisms of action of these drugs are similar, we can infer a similar relationship. However, this increased autophagy activity may reflect a mechanism for increasing tumor growth or a cellular compensation to inhibit its growth. Although evidence supports both views, we argued that autophagy allowed cancer cells to resist cell death, mainly due to DNA damage caused by cytotoxic drugs.

Autophagy reflects the cell's adaptation to survive and explains why chemotherapy generally induces autophagy functions. However, further research on autophagy inhibition is needed as it presents a viable treatment strategy, especially against drug-resistant populations that may arise from HL chemotherapy regimens.

Enforcing a well-differentiated state on cells requires tumor suppressor p53 activation as a key player in apoptosis induction and well differentiation. In addition, recent investigations showed a significant correlation between poorly differentiated status and higher expression of NANOG. Inducing the expression of NANOG and decreasing p53 level switch the status of liver cancer cells from well differentiated to poorly status. In this review, we highlighted p53 and NANOG cross-talk in hepatocellular carcinoma (HCC) which is regulated through mitophagy and makes it a novel molecular target to attenuate cancerous phenotype in the management of this tumor.

Resistance to oxaliplatin (L-OHP) is a major barrier in the treatment of colorectal cancer (CRC). Autophagy is the main cause of L-OHP tolerance in CRC cells.

The human colon cancer cell lines HCT116 and SW480 were treated with L-OHP to obtain the drug-resistant cell lines HCT116/L-OHP and SW480/L-OHP, respectively. To probe the relationship between autophagy and L-OHP tolerance of growth factor independent 1 (Gfi-1) and high-mobility group protein 1 (HMGB1) in CRC cells, gene knockout or overexpression was performed, and Western blotting was used to determine the levels of drug tolerance interrelated proteins. Transwell and CCK-8 assays were employed to analyze the proliferation of cancer cells. Immunofluorescence detection of LC3 reflected autophagy levels. Finally, the relationship between Gfi-1 and HMGB1 was detected by chromatin immunoprecipitation (ChIP).

Compared to normal CRC cells, L-OHP-tolerant CRC cells exhibited greater autophagy (8.2 times greater in HCT116/L-OHP cells and 7.4 times greater in SW480/L-OHP cells). In addition, we detected low levels of Gfi-1 (0.6-fold for HCT116/L-OHP cells and 0.4-fold for SW480/L-OHP cells), and OE-Gfi-1 decreased HMGB1 levels (0.6-fold for HCT116/L-OHP + OE-Gfi-1 cells and 0.5-fold for SW480/L-OHP + OE-Gfi-1 cells). The inhibition of Gfi-1 further enhanced cell viability (1.7 times in HCT116+sh-Gfi-1 cells and 1.2 times in SW480+sh-Gfi-1 cells) and invasion (1.8 times in HCT116+sh-Gfi-1 cells and 2.1 times in SW480+sh-Gfi-1 cells) in CRC cells, thus promoting oxaliplatin resistance in these cells. The autophagy inhibitor 3-MA reversed the above effects. Furthermore, we noted that Gfi-1 can restrain HMGB1 expression by binding to its promoter (0.5 times in HCT116+OE-Gfi-1 cells and 0.5 times in SW480+OE-Gfi-1 cells). The inhibitory influence of 3-MA on HMGB1 reversed the influence of Gfi-1 on autophagy and malignant progression in CRC cells.

Our study suggested that Gfi-1 inhibited HMGB1 to reduce CRC autophagy levels, increasing CRC sensitivity to L-OHP.

Cancer continues to be a prominent issue in the field of medicine, as demonstrated by recent studies emphasizing the significant role of autophagy in the development of cancer. Traditional Chinese Medicine (TCM) provides a variety of anti-tumor agents capable of regulating autophagy. However, the clinical application of autophagy-modulating compounds derived from TCM is impeded by their restricted water solubility and bioavailability. To overcome this challenge, the utilization of nanotechnology has been suggested as a potential solution. Nonetheless, the current body of literature on nanoparticles delivering TCM-derived autophagy-modulating anti-tumor compounds for cancer treatment is limited, lacking comprehensive summaries and detailed descriptions.

Up to November 2023, a comprehensive research study was conducted to gather relevant data using a variety of databases, including PubMed, ScienceDirect, Springer Link, Web of Science, and CNKI. The keywords utilized in this investigation included "autophagy", "nanoparticles", "traditional Chinese medicine" and "anticancer".

This review provides a comprehensive analysis of the potential of nanotechnology in overcoming delivery challenges and enhancing the anti-cancer properties of autophagy-modulating compounds in TCM. The evaluation is based on a synthesis of different classes of autophagy-modulating compounds in TCM, their mechanisms of action in cancer treatment, and their potential benefits as reported in various scholarly sources. The findings indicate that nanotechnology shows potential in enhancing the availability of autophagy-modulating agents in TCM, thereby opening up a plethora of potential therapeutic avenues.

Nanotechnology has the potential to enhance the anti-tumor efficacy of autophagy-modulating compounds in traditional TCM, through regulation of autophagy.

Hematological cancers include leukemia, myeloma and lymphoma and up to 178.000 new cases are diagnosed with these tumors each year. Different kinds of treatment including radiotherapy, chemotherapy, immunotherapy and stem cell transplantation have been employed in the therapy of hematological cancers. However, they are still causing death among patients. On the other hand, curcumin as an anti-cancer agent for the suppression of human cancers has been introduced. The treatment of hematological cancers using curcumin has been followed. Curcumin diminishes viability and survival rate of leukemia, myeloma and lymphoma cells. Curcumin stimulates apoptosis and G2/M arrest to impair progression of tumor. Curcumin decreases levels of matrix metalloproteinases in suppressing cancer metastasis. A number of downstream targets including VEGF, Akt and STAT3 undergo suppression by curcumin in suppressing progression of hematological cancers. Curcumin stimulates DNA damage and reduces resistance of cancer cells to irradiation. Furthermore, curcumin causes drug sensitivity of hematological tumors, especially myeloma. For targeted delivery of curcumin and improving its pharmacokinetic and anti-cancer features, nanostructures containing curcumin and other anti-cancer agents have been developed.

Hepatitis B virus (HBV) infection is a severe public health problem worldwide. The relationship between polymorphisms of autophagy-related 16-like 1 gene (ATG16L1) and autophagy-related gene 5 (ATG5) with susceptibility to the stage of HBV infection has been reported in different populations. Nevertheless, this association is not seen in the population of central China. This study recruited 452 participants, including 246 HBV-infected patients (139 chronically infected HBV without hepatocellular carcinoma [HCC] and 107 HBV-related HCC patients) and 206 healthy controls. Genotyping of ATG16L1 rs2241880 and ATG5 rs688810 were performed using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism, respectively. Our results indicated that the G allele of ATG16L1 rs2241880 was more frequent in healthy controls than in patients with chronicHBV infection. After adjusting for age and sex, an association between the ATG16L1 rs2241880 polymorphism and HBV infection was significant under the dominant and allele models (p = 0.009 and 0.003, respectively). However, no association between the ATG5 polymorphisms and HBV infection was observed. We also did not find a significant association between ATG16L1 and ATG5 polymorphisms and the progression of HBV-related HCC. Therefore, the genetic polymorphism of ATG16L1 rs2241880 may be associated with susceptibility to HBV infection in the population of central China.

Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ), the compounds with recognized ability to suppress autophagy, have been tested in experimental works and in clinical trials as adjuvant therapy for the treatment of tumors of different origin to increase the efficacy of cytotoxic agents. Such a strategy can be effective in overcoming the resistance of cancer cells to standard chemotherapy or anti-angiogenic therapy. This review presents the results of the combined application of CQ/HCQ with conventional chemotherapy drugs (doxorubicin, paclitaxel, platinum-based compounds, gemcitabine, tyrosine kinases and PI3K/Akt/mTOR inhibitors, and other agents) for the treatment of different malignancies obtained in experiments on cultured cancer cells, animal xenografts models, and in a few clinical trials. The effects of such an approach on the viability of cancer cells or tumor growth, as well as autophagy-dependent and -independent molecular mechanisms underlying cellular responses of cancer cells to CQ/HCQ, are summarized. Although the majority of experimental in vitro and in vivo studies have shown that CQ/HCQ can effectively sensitize cancer cells to cytotoxic agents and increase the potential of chemotherapy, the results of clinical trials are often inconsistent. Nevertheless, the pharmacological suppression of autophagy remains a promising tool for increasing the efficacy of standard chemotherapy, and the development of more specific inhibitors is required.

Cancer drug resistance remains a formidable challenge in modern oncology, necessitating innovative therapeutic strategies. The convergence of intricate regulatory networks involving long non-coding RNAs, microRNAs, and pivotal signaling pathways has emerged as a crucial determinant of drug resistance. This review underscores the multifaceted roles of lncRNAs and miRNAs in orchestrating gene expression and cellular processes, mainly focusing on their interactions with specific signaling pathways. Dysregulation of these networks leads to the acquisition of drug resistance, dampening the efficacy of conventional treatments. The review highlights the potential therapeutic avenues unlocked by targeting these non-coding RNAs. Developing specific inhibitors or mimics for lncRNAs and miRNAs, alone or in combination with conventional chemotherapy, emerges as a promising strategy. In addition, epigenetic modulators, immunotherapies, and personalized medicine present exciting prospects in tackling drug resistance. While substantial progress has been made, challenges, including target validation and safety assessment, remain. The review emphasizes the need for continued research to overcome these hurdles and underscores the transformative potential of lncRNA-miRNA interplay in revolutionizing cancer therapy.

Due to the proliferation of genetic testing, pathogenic germline variants predisposing to hereditary hematological malignancy syndrome (HHMS) have been identified in an increasing number of genes. Consequently, the field of HHMS is gaining recognition among clinicians and scientists worldwide. Patients with germline genetic abnormalities often have poor outcomes and are candidates for allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT using blood from a related donor should be carefully considered because of the risk that the patient may inherit a pathogenic variant. At present, we now face the challenge of incorporating these advances into clinical practice for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and optimizing the management and surveillance of patients and asymptomatic carriers, with the limitation that evidence-based guidelines are often inadequate. The 2016 revision of the WHO classification added a new section on myeloid malignant neoplasms, including MDS and AML with germline predisposition. The main syndromes can be classified into three groups. Those without pre-existing disease or organ dysfunction; DDX41, TP53, CEBPA, those with pre-existing platelet disorders; ANKRD26, ETV6, RUNX1, and those with other organ dysfunctions; SAMD9/SAMD9L, GATA2, and inherited bone marrow failure syndromes. In this review, we will outline the role of the genes involved in HHMS in order to clarify our understanding of HHMS.

Non-Small Cell Lung Cancer (NSCLC) is a malignancy with a significant prevalence and aggressive nature, posing a considerable challenge in terms of therapeutic interventions. Autophagy and apoptosis, two intricate cellular processes, are integral to NSCLC pathophysiology, each affecting the other through shared signaling pathways. Phytol (Phy) and α-bisabolol (Bis) have shown promise as potential anticancer agents individually, but their combined effects in NSCLC have not been extensively investigated.

The present study was to examine the synergistic impact of Phy and Bis on NSCLC cells, particularly in the context of autophagy modulation, and to elucidate the resulting differential protein expression using LCMS/ MS analysis.

The A549 cell lines were subjected to the patented effective concentration of Phy and Bis, and subsequently, the viability of the cells was evaluated utilizing the MTT assay. The present study utilized real-time PCR analysis to assess the expression levels of crucial apoptotic genes, specifically Bcl-2, Bax, and Caspase-9, as well as autophagy-related genes, including Beclin-1, SQSTM1, Ulk1, and LC3B. The confirmation of autophagy marker expression (Beclin-1, LC3B) and the autophagy-regulating protein SQSTM1 was achieved through the utilization of Western blot analysis. Differentially expressed proteins were found using LC-MS/MS analysis.

The combination of Phy and Bis demonstrated significant inhibition of NSCLC cell growth, indicating their synergistic effect. Real-time PCR analysis revealed a shift towards apoptosis, with downregulation of Bcl-2 and upregulation of Bax and Caspase-9, suggesting a shift towards apoptosis. Genes associated with autophagy regulation, including Beclin-1, SQSTM1 (p62), Ulk1, and LC3B, showed significant upregulation, indicating potential induction of autophagy. Western blot analysis confirmed increased expression of autophagy markers, such as Beclin-1 and LC3B, while the autophagy-regulating protein SQSTM1 exhibited a significant decrease. LC-MS/MS analysis revealed differential expression of 861 proteins, reflecting the modulation of cellular processes. Protein-protein interaction network analysis highlighted key proteins involved in apoptotic and autophagic pathways, including STOML2, YWHAB, POX2, B2M, CDA, CAPN2, TXN, ECHS1, PEBP1, PFN1, CDC42, TUBB1, HSPB1, PXN, FGF2, and BAG3, emphasizing their crucial roles. Additionally, PANTHER pathway analysis uncovered enriched pathways associated with the differentially expressed proteins, revealing their involvement in a diverse range of biological processes, encompassing cell signaling, metabolism, and cellular stress responses.

The combined treatment of Phy and Bis exerts a synergistic inhibitory effect on NSCLC cell growth, mediated through the interplay of apoptosis and autophagy. The differential protein expression observed, along with the identified proteins and enriched pathways, provides valuable insights into the underlying molecular mechanisms. These findings offer a foundation for further exploration of the therapeutic potential of Phy and Bis in the management of NSCLC.

Drug resistance is one of the main challenges in cancer treatment. Long non coding RNAs (lncRNAs) play a complex and precise regulatory role in regulating drug resistance of cancer. The common ways of lncRNA regulating drug resistance of cancer involve ATP binding transporter overexpression, abnormal DNA damage response, tumor cell apoptosis, accumulation of epithelial mesenchymal transformation and cancer stem cell formation. Moreover, studies on exosomal lncRNAs regulating cancer drug resistance are developed in recent years. Further study on the role and mechanism of lncRNAs drug resistance in cancer will help clinical cancer treatment program and explore new treatment methods. This paper reviews recent advances in lncRNAs regulating drug resistance of cancer, especially the role of exosomal lncRNAs.

Cisplatin, a classical platinum-based chemotherapy agent, has been a frontline treatment for various cancers for decades. However, its effectiveness has been hindered by the development of resistance, leading to cancer relapse. Addressing this challenge is crucial for both clinical practice and research. Hence, the imperative to unravel the intricate mechanisms underpinning cisplatin resistance and to uncover novel strategies to overcome this barrier holds immense significance. Within this review, we summarized the classification of platinum agents, highlighting their roles in therapeutic landscapes. We discussed the diverse mechanisms behind cisplatin resistance, including diminished intracellular cisplatin accumulation, intracellular detoxification, DNA repair, autophagy responses, heat shock proteins, tumor microenvironment, cancer stem cells, epigenetic regulation, ferroptosis resistance, and metabolic reprogramming. Drawing from this comprehensive understanding, we offered a series of prospective solutions to surmount cisplatin resistance and consequently mitigate the specter of disease recurrence within the realm of clinical cancer therapy.

Cisplatin (CDDP) is a mainstay chemotherapeutic agent for OS treatment, but drug resistance has become a hurdle to limit its clinical effect. Autophagy plays an important role in CDDP resistance in OS, and in the present study we explored the role of ANXA2 and Rac1 in dictating CDDP sensitivity in OS cells.

ANXA2 and Rac1 expression levels were examined by Western blot and autophagy induction was detected by transmission electron miscroscope (TEM) in the clinical samples and OS cell lines. CDDP resistant cells were established by exposing OS cells to increasing doses of CDDP. The effects of ANXA2 and Rac1 knockdown on CDDP sensitivity were evaluated in the cell and animal models.

Reduced autophagy was associated with the increased expression of ANXA2 and Rac1 in CDDP resistant OS tumor samples and cells. Autophagy suppression promoted CDDP resistance and inducing autophagy re-sensitized the resistant cells to CDDP treatment in vitro and in vivo. Further, knocking down ANXA2 or Rac1 re-activated autophagy and attenuated CDDP resistance in OS cells. We further demonstrated that CDDP resistant OS cells displayed a poorer osteogenic differentiation state when compared to the parental cell lines, which was significantly reversed by autophagy re-activation and ANXA2 or Rac1 silencing.

Our findings revealed a complicated interplay of ANXA2/Rac1, autophagy induction, and osteogenic differentiation in dictating CDDP resistance in OS cells, suggesting ANXA2 and Rac1 as promising targets to modulate autophagy and overcome CDDP resistance in OS cells.

The mechanism of acquired resistance of tamoxifen in endocrine therapy of breast cancer is not fully understood. In this study, we investigated the genomic changes in acquired tamoxifen-resistant cell lines.

Tamoxifen-resistant subclones (MCF-7R) derived from parent MCF-7 cells, which is an ER(+) breast cancer cell line, cultured with 4-hydrotamoxifen more than 6 months were used to obtain genomic alterations. Cell growth, microarray, and quantitative real-time PCR (q-RTPCR) assays were conducted. Additionally, the ITGB1 function was investigated in MCF-7R cells and MCF-7R ITGB1-silenced subclones using MTT and Transwell assays. Online pathway analysis was performed to assess the genetic characteristics of tamoxifen resistance.

The gene expression profile of the tamoxifen-resistant cell line was considerably changed compared to the tamoxifen-sensitive cell line. Of 4102 genes with altered expressions, 1986 genes were upregulated, whereas 2116 were downregulated. The ITGB1 expression in MCF-7R cells was higher than that in MCF-7 cells. Interestingly, ITGB1 silencing partially rescued the sensitivity of MCF-7R cells to tamoxifen and reduced their motility. The activation of the β1-integrin signaling pathway was probably responsible for this phenomenon.

Our data confirm the presence of alterations in the genes of tamoxifen-resistance breast cancer cells. ITGB1 probably partially contributes to tamoxifen resistance and cell motility via the β1-integrin signaling pathway. Thus, ITGB1 may be a potential target for the improvement of anti-hormone therapy reaction in ER(+) breast cancer patients.

Drug resistance continues to be a significant problem in cancer therapy, leading to relapse and associated mortality. Although substantial progress has been made in understanding drug resistance, significant knowledge gaps remain concerning the molecular underpinnings that drive drug resistance and which processes are unique to certain drug classes. The NCI-60 cell line panel program has evaluated the activity of numerous anticancer agents against many common cancer cell line models and represents a highly valuable resource to study intrinsic drug resistance. Furthermore, great efforts have been undertaken to collect high-quality omics datasets to characterize these cell lines. The current study takes these two sources of data-drug response and omics profiles-and uses a multi-omics investigation to uncover molecular networks that differentiate cancer cells that are sensitive or resistant to antifolates, which is a commonly used class of anticancer drugs. Results from a combination of univariate and multivariate analyses showed numerous metabolic processes that differentiate sensitive and resistant cells, including differences in glycolysis and gluconeogenesis, arginine and proline metabolism, beta-alanine metabolism, purine metabolism, and pyrimidine metabolism. Further analysis using multivariate and integrated pathway analysis indicated purine metabolism as the major metabolic process separating cancer cells sensitive or resistant to antifolates. Additional pathways differentiating sensitive and resistant cells included autophagy-related processes (e.g., phagosome, lysosome, autophagy, mitophagy) and adhesion/cytoskeleton-related pathways (e.g., focal adhesion, regulation of actin cytoskeleton, tight junction). Volcano plot analysis and the receiver operating characteristic (ROC) curves of top selected variables differentiating Q1 and Q4 revealed the importance of genes involved in the regulation of the cytoskeleton and extracellular matrix (ECM). These results provide novel insights toward mechanisms of intrinsic antifolate resistance as it relates to interactions between nucleotide metabolism, autophagy, and the cytoskeleton. These processes should be evaluated in future studies to potentially derive novel therapeutic strategies and personalized treatment approaches to improve antifolate response.

Autophagy is an evolutionarily conserved process critical in maintaining cellular homeostasis. Recently, the anticancer potential of autophagy inducers, including phytochemicals, was suggested. Indicaxanthin is a betalain pigment found in prickly pear fruit with antiproliferative and pro-apoptotic activities in colorectal cancer cells associated with epigenetic changes in selected methylation-silenced oncosuppressor genes. Here, we demonstrate that indicaxanthin induces the up-regulation of the autophagic markers LC3-II and Beclin1, and increases autophagolysosome production in Caco-2 cells. Methylomic studies showed that the indicaxanthin-induced pro-autophagic activity was associated with epigenetic changes. In addition to acting as a hypermethylating agent at the genomic level, indicaxanthin also induced significant differential methylation in 39 out of 47 autophagy-related genes, particularly those involved in the late stages of autophagy. Furthermore, in silico molecular modelling studies suggested a direct interaction of indicaxanthin with Bcl-2, which, in turn, influenced the function of Beclin1, a key autophagy regulator. External effectors, including food components, may modulate the epigenetic signature of cancer cells. This study demonstrates, for the first time, the pro-autophagic potential of indicaxanthin in human colorectal cancer cells associated with epigenetic changes and contributes to outlining its potential healthy effect in the pathophysiology of the gastrointestinal tract.

The above article, published online on 19 September 2022 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/abs/10.1002/jbt.23211), has been retracted by agreement between the authors, the journal Editor in Chief, Hari Bhat, and Wiley Periodicals, LLC. The article is being retracted at the authors' request because some of the data underlying this article refer to a different cell line from the one reported in it. As a result, the article's conclusions do not accurately reflect the full data and cannot be considered reliable.

Pancreatic ductal adenocarcinoma (PDAC) remains an extremely aggressive disease characterized by rapidly acquired multi-drug resistance, including to first-line chemotherapeutic agent gemcitabine. Autophagy is a process that is often exploited by cancer and is one of several intrinsic factors associated with resistance to gemcitabine. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of factors including Valosin-containing protein (VCP). VCP has been reported to play an important role in autophagic flux. In this study, we investigated whether the repression of VCP through miR-198 administration disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment in vitro. Moreover, we used LGA-PEI (LPNP) nanoparticles to effectively administer miR-198 to tumors in vivo, inducing tumor sensitization to gemcitabine and leading to a significant reduction in tumor burden and metastases and a concomitant downregulation of VCP expression and autophagy maturation. Our results indicate a potential therapeutic strategy for targeting gemcitabine resistant PDAC and establishes the use of LPNPs for effective therapeutic delivery of nucleic acids in vitro and in vivo.

The use of 5-fluorouracil (5-FU) is associated with multifaceted challenges and poor pharmacokinetics. Accordingly, our study was designed to prepare 5-FU nanogel as a new form of the colon cancer chemotherapeutic drug 5-FU using polyacrylic acid and gelatin hybrid nanogel as efficient drug carriers. Alongside the in vivo chemotherapeutic evaluation, the anti-proliferative and anti-apoptotic efficacy were carried out for 5-FU nanogel against 1,2-dimethylhydrazine (DMH, 20 mg/kg) and γ-radiation (4 Gy)-prompted colon dysplasia in rats compared to 5-FU. The morphology and size of 5-FU nanogel were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) in addition to cytotoxicity assay. The expression of phosphoinositide-3-kinase (PI3K)/Akt, mammalian target of rapamycin (mTOR); Toll-like receptor2 (TLR2)/nuclear factor kappa B), adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its downstream autophagy-related genes in addition to apoptotic markers were measured in colon tissues. Results: 5-FU nanogel reduced the levels of the TLR2/ NF-κβ as well as the expression of PI3K/AKT/mTOR. Moreover, it promoted autophagy through the activation of the AMPK and its downstream targets which consequently augmented the intrinsic and extrinsic apoptotic pathways. Conclusion: Collectively, these data might strengthen the therapeutic potential of 5-FU nanogel which can be used as an antitumor product for colon cancer.

Natural compounds originating from plants offer a wide range of pharmacological potential and have traditionally been used to treat a wide range of diseases including cancer. Tanshinone IIA (Tan IIA), a bioactive molecule found in the roots of the Traditional Chinese Medicine (TCM) herb Salvia miltiorrhiza, has been shown to have remarkable anticancer properties through several mechanisms, such as inhibition of tumor cell growth and proliferation, metastasis, invasion, and angiogenesis, as well as induction of apoptosis and autophagy. It has demonstrated excellent anticancer efficacy against cell lines from breast, cervical, colorectal, gastric, lung, and prostate cancer by modulating multiple signaling pathways including PI3K/Akt, JAK/STAT, IGF-1R, and Bcl-2-Caspase pathways. This review focuses on the role of Tan IIA in the treatment of various cancers, as well as the underlying molecular mechanisms.

Colorectal cancer (CRC) is one of the commonest neoplasms worldwide, which its pathogenesis is strongly correlated with p53 mutations. Antioxidants are believed to decelerate the CRC progression, possibly through interfering with p53 and its downstream target genes and mechanisms. Regarding the potential antioxidant effects of bilirubin, as an incredible endogenous antioxidant, we sought to investigate how bilirubin affected the expression levels of p53 protein and its downstream target genes, including Mdm2, Bcl-2, BECN1 and LC3, in LS180 and SW480 cell culture models of CRC.

Using the MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium bromide) assay, 50 and 100 μM concentrations of bilirubin were determined to be non-toxic for both LS180 and SW480 cell lines. Western blot analysis was employed to evaluate the protein expression levels of p53. The results revealed that p53 protein levels were higher in LS180 cells treated with bilirubin compared to the control group. Notwithstanding, in SW480 cells, no considerable changes were observed in p53 protein levels of treated cells compared to the control ones. The quantitative reverse transcriptase-polymerase chain reaction (q RT-PCR) method was used to measure the mRNA expression levels of the apoptosis/autophagy-related genes, Mdm2, Bcl-2, BECN1, and LC3 , as the p53's downstream target genes. Consequently, the expression of Bcl-2 and Mdm2 genes were affected by p53, while BECN1 and LC3 expression levels were decreased in both cell lines.

Bilirubin is an endogenous antioxidant with significant anti-tumor effects in the studied CRC cell lines, probably through the regulation of p53 protein expression levels and subsequent control of apoptosis and autophagy, as two key processes involved in cell survival and progression of tumor cells.

Clinically, although chemotherapy is one of the most commonly used methods of treating tumors, chemotherapeutic drugs can induce autophagic flux and increase tumor cell resistance, leading to drug tolerance. Therefore, theoretically, inhibiting autophagy may improve the efficacy of chemotherapy. The discovery of autophagy regulators and their potential application as adjuvant anti-cancer drugs is of substantial importance. In this study, we clarified that Fangjihuangqi Decoction (FJHQ, traditional Chinese medicine) is an autophagy inhibitor, which can synergistically enhance the effect of cisplatin and paclitaxel on non-small cell lung cancer (NSCLC) cells.

We observed the changes of autophagy level in NSCLC cells under the effect of FJHQ, and verified the level of the autophagy marker protein and cathepsin. Apoptosis was detected after the combination of FJHQ with cisplatin or paclitaxel, and NAC (ROS scavenger) was further used to verify the activation of ROS-MAPK pathway by FJHQ.

We observed that FJHQ induced autophagosomes in NSCLC cells and increased the levels of P62 and LC3-II protein expression in a concentration- and time-gradient-dependent manner, indicating that autophagic flux was inhibited. Co-localization experiments further showed that while FJHQ did not inhibit autophagosome and lysosome fusion, it affected the maturation of cathepsin and thus inhibited the autophagic pathway. Finally, we found that the combination of FJHQ with cisplatin or paclitaxel increased the apoptosis rate of NSCLC cells, due to increased ROS accumulation and further activation of the ROS-MAPK pathway. This synergistic effect could be reversed by NAC.

Collectively, these results demonstrate that FJHQ is a novel late-stage autophagy inhibitor that can amplify the anti-tumor effect of cisplatin and paclitaxel against NSCLC cells.

Despite effective new therapies, adaptive resistance remains the main obstacle in acute myelogenous leukemia (AML) therapy. Autophagy induction is a key mechanism for adaptive resistance. Leukemic blasts at diagnosis express higher levels of the apical autophagy kinase ULK1 compared with normal hematopoietic cells. Exposure to chemotherapy and targeted agents upregulate ULK1, hence we hypothesize that developing ULK1 inhibitors may present the unique opportunity for clinical translation of autophagy inhibition. Accordingly, we demonstrate that ULK1 inhibition, by genetic and pharmacologic means, suppresses treatment-induced autophagy, overcomes adaptive drug-resistance, and synergizes with chemotherapy and emerging antileukemia agents like venetoclax (ABT-199). The study next aims at exploring the underlying mechanisms. Mechanistically, ULK1 inhibition downregulates MCL1 antiapoptotic gene, impairs mitochondrial function and downregulates components of the CD44-xCT system, resulting in impaired reactive oxygen species (ROS) mitigation, DNA damage, and apoptosis. For further validation, several mouse models of AML were generated. In these mouse models, ULK1 deficiency impaired leukemic cell homing and engraftment, delayed disease progression, and improved survival. Therefore, in the study, we validated our hypothesis and identified ULK1 as an important mediator of adaptive resistance to therapy and an ideal candidate for combination therapy in AML. Therefore, we propose ULK1 inhibition as a therapeutically relevant treatment option to overcome adaptive drug-resistance in AML.

ULK1 drives a cell-intrinsic adaptive resistance in AML and targeting ULK1-mediated autophagy can synergize with existing and emerging AML therapies to overcome drug-resistance and induce apoptosis.

Osteosarcoma is a malignant bone tumor occurring in adolescents. Surgery combined with adjuvant or neoadjuvant chemotherapy is the standard treatment. However, systemic chemotherapy is associated with serious side effects and a high risk of postoperative tumor recurrence, leading to a high amputation rate and mortality in cancer patients. Implant materials that can simultaneously repair large bone defects and prevent osteosarcoma recurrence are in urgent need. Herein, an intelligent system comprising 3D-printed titanium scaffold (TS) and pH-responsive PEGylated paclitaxel prodrugs was fabricated for bone defect reconstruction and recurrence prevention following osteosarcoma surgery. The drug-loaded implants exhibited excellent stability and biocompatibility for supporting the activity of bone stem cells under normal body fluid conditions and the rapid release of drugs in response to faintly acidic environments. An in vitro study demonstrated that five human osteosarcoma cell lines could be efficiently eradicated by paclitaxel released in an acidic microenvironment. Using mice models, we demonstrated that the drug-loaded TS can enable a pH-responsive treatment of postoperative tumors and effectively prevent osteosarcoma recurrence. Therefore, local implantation of this composite scaffold may be a promising topical therapeutic method to prevent osteosarcoma recurrence.

TRPC1 enhances cell proliferation and migration in non-small cell lung cancer (NSCLC); however, its effect on NSCLC chemoresistance and stemness remains to be determined. The aim of the current study was to investigate the effect of TRPC1 on NSCLC chemoresistance and stemness and to determine the underlying mechanism of action. Cisplatin-resistant A549 (A549/CDDP) and H460 (H460/CDDP) cells were first established and were then transfected with negative control small interfering (si)RNA (si-NC) or TRPC1 siRNA (si-TRPC1). Cells were then treated with 740 Y-P, a PI3K/Akt agonist. Subsequently, the sensitivity of A549/CDDP and H460/CDDP cells to CDDP was evaluated. Furthermore, the expression levels of CD133 and CD44, and sphere formation ability were also determined. The results showed that the half-maximal inhibitory concentration (IC₅₀) of CDDP was significantly higher in A549/CDDP cells compared with A549 cells and in H460/CDDP cells compared with H460 cells. TRPC1 silencing decreased the IC₅₀ value of CDDP compared with the si-NC group in A549/CDDP (11.78 vs. 21.58 µM; P<0.01) and H460/CDDP (23.76 vs. 43.11 µM; P<0.05) cells. Additionally, TRPC1 knockdown in both cell lines decreased the number of spheres formed compared with the si-NC group. Furthermore, compared with the si-NC group, A549/CDDP cells transfected with si-TRPC1 exhibited decreased levels of both CD133 (P<0.01) and CD44 (P<0.05). However, only CD133 (P<0.05) was downregulated in TRPC1-depleted H460/CDDP cells compared with the si-NC group. In addition, TRPC1 knockdown repressed PI3K/AKT signaling compared with the si-NC group in both A549/CDDP and H460/CDDP cells (all P<0.05). Finally, cell treatment with 740 Y-P reversed the effect of TRPC1 knockdown on PI3K/AKT signaling, chemoresistance, and cancer stemness in A549/CDDP and H460/CDDP cells (all P<0.05). In conclusion, the results of the current study suggested that targeting TRPC1 could attenuate cancer stemness and chemoresistance via suppression of PI3K/AKT signaling in NSCLC.

The major challenges in Osteosarcoma (OS) therapy are its heterogeneity and drug resistance. The development of new therapeutic approaches to overcome the major growth mechanisms of OS is urgently needed. The search for specific molecular targets and promising innovative approaches in OS therapy, including drug delivery methods, is an urgent problem. Modern regenerative medicine focuses on harnessing the potential of mesenchymal stem cells (MSCs) because they have low immunogenicity. MSCs are important cells that have received considerable attention in cancer research. Currently, new cell-based methods for using MSCs in medicine are being actively investigated and tested, especially as carriers for chemotherapeutics, nanoparticles, and photosensitizers. However, despite the inexhaustible regenerative potential and known anticancer properties of MSCs, they may trigger the development and progression of bone tumors. A better understanding of the complex cellular and molecular mechanisms of OS pathogenesis is essential to identify novel molecular effectors involved in oncogenesis. The current review focuses on signaling pathways and miRNAs involved in the development of OS and describes the role of MSCs in oncogenesis and their potential for antitumor cell-based therapy.