Autophagy In Tumor Cells Research Articles

In situ autophagy regulation in synergy with phototherapy for breast cancer treatment

Autophagy is an important factor in reducing the efficacy of tumor phototherapy (including PTT and PDT). Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT. This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy. To achieve this goal, we first synthesized TRANSFERRIN (Tf) biomimetic mineralized nano-tellurium (Tf-Te) as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly. The autophagy inhibitor hydroxychloroquine (HCQ) and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ. After entering breast cancer cells through the “self-guidance system”, Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation, to efficiently induce PTT/PDT effect. Meanwhile, the disulfide bond broke down in response to GSH, and the nanoparticles disintegrated to release Fe2+ and HCQ at fixed points. They simultaneously induce lysosomal alkalinization and increased osmotic pressure, effectively inhibit autophagy, and synergistically enhance the therapeutic effect of phototherapy. In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6% on 4T1 tumor-bearing mice. This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.

Developing a Hetero-Trinuclear Erbium(III)-Copper(II) Complex Based on Apoferritin: Targeted Photoacoustic Imaging and Multimodality Therapy of Tumor.

For the integration of targeted diagnosis and treatment of tumor, we innovatively designed and synthesized a single-molecule hetero-multinuclear Er(III)-Cu(II) complex (ErCu2) and then constructed an ErCu2@apoferritin (AFt) nanoparticle (NP) delivery system. ErCu2 and ErCu2@AFt NPs not only provided an evident photoacoustic imaging (PAI) signal of the tumor but also effectively inhibited tumor growth by integrating photothermal therapy, chemotherapy, and immunotherapy. ErCu2@AFt NPs improved the targeting ability and decreased the systemic toxicity of ErCu2 in vivo. Furthermore, we confirmed that ErCu2 and ErCu2@AFt NPs inhibited tumor growth by inducing apoptosis and autophagy of tumor cells and activating the immune system. The study not only provides a novel strategy to develop therapeutic metal agents but also reveals their potential for targeted accurate diagnosis and multimodality therapy of cancer.

Autophagy as a Target for Non-Immune Intrinsic Functions of Programmed Cell Death-Ligand 1 in Cancer.

Autophagy is a catabolic process that is essential to the maintenance of homeostasis through the cellular recycling of damaged organelles or misfolded proteins, which sustains energy balance. Additionally, autophagy plays a dual role in modulating the development and progression of cancer and inducing a survival strategy in tumoral cells. Programmed cell death-ligand 1 (PD-L1) modulates the immune response and is responsible for maintaining self-tolerance. Because tumor cells exploit the PD-L1-PD-1 interaction to subvert the immune response, immunotherapy has been developed based on the use of PD-L1-blocking antibodies. Recent evidence has suggested a bidirectional regulation between autophagy and PD-L1 molecule expression in tumor cells. Moreover, the research into the intrinsic properties of PD-L1 has highlighted new functions that are advantageous to tumor cells. The relationship between autophagy and PD-L1 is complex and still not fully understood; its effects can be context-dependent and might differ between tumoral cells. This review refines our understanding of the non-immune intrinsic functions of PD-L1 and its potential influence on autophagy, how these could allow the survival of tumor cells, and what this means for the efficacy of anti-PD-L1 therapeutic strategies.

Autophagy-amplifying nanoparticles evoke immunogenic cell death combined with anti-PD-1/PD-L1 for residual tumors immunotherapy after RFA

Incomplete radiofrequency ablation (IRFA) triggers mild protective autophagy in residual tumor cells and results in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and causes resistance to anti-PD-1/PDL1 therapy, which bringing a great clinical challenge in residual tumors immunotherapy. Mild autophagy activation can promote cancer cell survival while further amplification of autophagy contributes to immunogenic cell death (ICD). To this regard, we constructed active targeting zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) loaded with STF62247 or both STF62247 and BMS202, namely STF62247@ZIF-8/PEG-FA (SZP) or STF62247-BMS202@ZIF-8/PEG-FA (SBZP) NPs. We found that SZP NPs inhibited proliferation and stimulated apoptosis of residual tumor cells exposed to sublethal heat stress in an autophagy-dependent manner. Further results discovered that SZP NPs could amplify autophagy in residual tumor cells and evoke their ICD, which dramatically boosted the maturation of dendritic cells (DCs). Through vaccination experiments, we found for the first time that vaccination with heat + SZP treatment could efficiently suppress the growth of new tumors and establish long-term immunological memory. Furthermore, SBZP NPs could remarkably promote the ICD of residual tumor cells, obviously activate the anti-tumor immune microenvironment, and significantly inhibit the growth of residual tumors. Thus, amplified autophagy coupled with anti-PD-1/PDL1 therapy is potentially a novel strategy for treating residual tumors after IRFA.Graphical

Pentacyclic triterpene-amino acid derivatives induced apoptosis and autophagy in tumor cells, affected the JNK and PI3K/AKT/mTOR pathway

A series of pentacyclic triterpene-amino acid derivatives were synthesized and tested for anti-proliferative activity. The results showed that most of the target compounds had good anti-proliferative activity. 2c did not contain protecting groups and hydrochloride, had excellent cytotoxicity, so it had been selected for further study in the mechanism of action in T24 cells. The data from transcriptome sequencing indicated that 2c was found to be closely related to apoptosis and autophagy. Observation of fluorescence staining and analysis from flow cytometry demonstrated that 2c induced apoptosis and cause cell cycle arrest in S/G2 phase in T24 cells. Molecular mechanism studies exhibited that 2c induced apoptosis in the intrinsic and extrinsic pathways. 2c also induced cellular autophagy in T24 cells. Results from Western Blotting showed that 2c could activate JNK pathway and inhibit PI3K/AKT/mTOR pathway. In conclusion, 2c was deserved further investigation in the field of anti-tumor.

Three-dimensional growth sensitizes breast cancer cells to treatment with ferroptosis-promoting drugs

Drugs causing ferroptosis, iron-mediated cell death, represent promising tools for cancer treatment. While exploring the effect of these drugs on breast cancer (BC), we found that a ferroptosis-inducing drug erastin dramatically inhibits tumorigenicity of human BC cells in mice but when used at a concentration known to effectively kill other cell types only modestly reduces such growth in 2D monolayer culture. BCs grow in vivo as 3D masses, and we found that ferroptosis inducers erastin and sulfasalazine inhibit growth of multiple human BC cell lines in 3D culture significantly stronger than in 2D culture. To understand the mechanism of this differential effect, we found that ferroptosis inducers upregulate mRNAs encoding multiple direct and indirect autophagy stimulators, such as ATG16L2, ATG9A, ATG4D, GABARAP, SQSTM/p62, SEC23A and BAX, in tumor cells growing in 2D but not in 3D culture. Furthermore, these drugs promoted autophagy of tumor cells growing in a 2D but not in a 3D manner. We observed that pharmacological inhibition of autophagy-stimulating protein kinase ULK1 or RNA interference-mediated knockdown of autophagy mediator ATG12 significantly sensitized tumor cells to erastin treatment in 2D culture. We also found that ferroptosis-promoting treatments upregulate heme oxygenase-1 (HO-1) in BC cells. HO-1 increases cellular free iron pool and can potentially promote ferroptosis. Indeed, we observed that HO-1 knockdown by RNA interference reversed the effect of ferroptosis inducers on BC cell 3D growth. Hence, the effect of these drugs on such growth is mediated by HO-1. In summary, autophagy triggered by ferroptosis-promoting drugs reduces their ability to kill BC growing in a 2D manner. This protection mechanism is inhibited in BC cells growing as a 3D mass, and ferroptosis-promoting drugs kill such cells more effectively. Moreover, this death is mediated by HO-1. Thus, ferroptosis induction represents a promising strategy for blocking 3D BC growth.

Ubiquitination Is a Novel Post-Translational Modification of VMP1 in Autophagy of Human Tumor Cells.

Autophagy is a tightly regulated catabolic process involved in the degradation and recycling of proteins and organelles. Ubiquitination plays an important role in the regulation of autophagy. Vacuole Membrane Protein 1 (VMP1) is an essential autophagy protein. The expression of VMP1 in pancreatic cancer stem cells carrying the activated Kirsten rat sarcoma viral oncogene homolog (KRAS) triggers autophagy and enables therapy resistance. Using biochemical and cellular approaches, we identified ubiquitination as a post-translational modification of VMP1 from the initial steps in autophagosome biogenesis. VMP1 remains ubiquitinated as part of the autophagosome membrane throughout autophagic flux until autolysosome formation. However, VMP1 is not degraded by autophagy, nor by the ubiquitin-proteasomal system. Mass spectrometry and immunoprecipitation showed that the cell division cycle protein cdt2 (Cdt2), the substrate recognition subunit of the E3 ligase complex associated with cancer, cullin-RING ubiquitin ligase complex 4 (CRL4), is a novel interactor of VMP1 and is involved in VMP1 ubiquitination. VMP1 ubiquitination decreases under the CRL inhibitor MLN4924 and increases with Cdt2 overexpression. Moreover, VMP1 recruitment and autophagosome formation is significantly affected by CRL inhibition. Our results indicate that ubiquitination is a novel post-translational modification of VMP1 during autophagy in human tumor cells. VMP1 ubiquitination may be of clinical relevance in tumor-cell-therapy resistance.

Research progress on the anti-tumor effect of Naringin.

Naringin is a kind of natural dihydro flavone, which mainly exists in citrus fruits of the Rutaceae family, as well as traditional Chinese medicines such as trifoliate orange, fingered citron, exocarpium citri grandis, and rhizoma dynamite. Modern pharmacological studies have shown that Naringin has excellent anti-tumor activity. Through reviewing the relevant literature at home and abroad in recent years, we summarized the pharmacological mechanism of Naringin to play an anti-cancer role in blocking tumor cell cycle, inhibiting tumor cell proliferation, inducing tumor cell apoptosis, inhibiting tumor cell invasion and metastasis, inducing tumor cell autophagy, reversing tumor cell drug resistance and enhancing chemotherapeutic drug sensitivity, as well as anti-inflammatory to prevent canceration, alleviate Adverse drug reaction of chemotherapy, activate and strengthen immunity, It provides theoretical basis and reference basis for further exploring the anticancer potential of Naringin and its further development and utilization.

Antitumor activity of miR-188-3p in gastric cancer is achieved by targeting CBL expression and inactivating the AKT/mTOR signaling.

Altered miR-188-3p expression has been observed in various human cancers. To investigate the miR-188-3p expression, its roles, and underlying molecular events in gastric cancer. Fifty gastric cancer and paired normal tissues were collected to analyze miR-188-3p and CBL expression. Normal and gastric cancer cells were used to manipulate miR-188-3p and CBL expression through different assays. The relationship between miR-188-3p and CBL was predicted bioinformatically and confirmed using a luciferase gene reporter assay. A Kaplan-Meier analysis was used to associate miR-188-3p or CBL expression with patient survival. A nude mouse tumor cell xenograft assay was used to confirm the in vitro data. MiR-188-3p was found to be lower in the plasma of gastric cancer patients, tissues, and cell lines compared to their healthy counterparts. It was associated with overall survival of gastric cancer patients (P < 0.001), tumor differentiation (P < 0.001), lymph node metastasis (P = 0.033), tumor node metastasis stage (I/II vs III/IV, P = 0.024), and American Joint Committee on Cancer stage (I/II vs III/IV, P = 0.03). Transfection with miR-188-3p mimics reduced tumor cell growth and invasion while inducing apoptosis and autophagy. CBL was identified as a direct target of miR-188-3p, with its expression antagonizing the effects of miR-188-3p on gastric cancer (GC) cell proliferation by inducing tumor cell apoptosis and autophagy through the inactivation of the Akt/mTOR signaling pathway. The in vivo data confirmed antitumor activity via CBL downregulation in gastric cancer. The current data provides ex vivo, in vitro, and in vivo evidence that miR-188-3p acts as a tumor suppressor gene or possesses antitumor activity in GC.

Design, synthesis and antitumour activity evaluation of novel dolutegravir derivatives.

Based on the modification of the structure of dolutegravir, we introduced 1,2,3-triazole moieties with different substituted groups and obtained a lot of novel dolutegravir derivatives. The activity of A549 cells treated with the derivatives was examined, and most compounds showed good inhibitory effects. Among them, compounds 4b and 4g were the most effective, and inhibited the growth of A549 cells with IC50 values of 8.72 ± 0.11μM and 12.97 ± 0.32μM, respectively. In addition, compound 4g induced apoptosis and clonal suppression in A549 tumor cells. Compound 4g also activated the LC3 signaling pathway to induce autophagy in tumor cells, and activated the γ-H2AX signaling pathway to induce DNA damage in tumor cells.

Molecular Mechanism Underlying the Action of a Celastrol-Loaded Layered Double Hydroxide-Coated Magnesium Alloy in Osteosarcoma Inhibition and Bone Regeneration.

Osteosarcoma (OS) is a malignant bone tumor that threatens human health. Surgical removal of the tumor and followed by implantation with a graft is the golden standard for its clinical treatment. However, avoiding recurrence by enhancing the antitumor properties of the implants and improving osteogenesis around the implants remain a challenge. Here, we developed a layered double hydroxide (LDH)-coated magnesium (Mg) alloy and loaded it with celastrol. The celastrol-loaded Mg alloy exhibited enhanced corrosion resistance and sustained release of celastrol. In vitro cell culture suggested that the modified Mg alloy loaded with an appropriate amount of celastrol significantly inhibited the proliferation and migration of bone tumor cells while having little influence on normal cells. A mechanistic study revealed that the celastrol-loaded Mg alloy upregulated reactive oxygen species (ROS) generation in bone tumor cells, resulting in mitochondrial dysfunction due to reduced membrane potential, thereby inducing bone tumor cell apoptosis. Furthermore, it was found that celastrol-induced autophagy in tumor cells inhibited cell apoptosis in the initial 6 h. After ≥12 h of culture, inhibition of the PI3K-Akt-mTOR signaling pathway was noted, resulting in excessive autophagy in tumor cells, finally causing cell apoptosis. The celatsrol-loaded Mg alloy also exhibited effective antitumor properties in a subcutaneous tumor model. In vitro tartrate-resistant acid phosphatase (TRAP) staining and gene expression results revealed that the modified Mg alloy reduced the viability of osteoclasts, inducing a potential pathway for the increased bone regeneration around the modified Mg alloy seen in vivo. Together, the results of our study show that the celatsrol-loaded Mg alloy might be a promising implant for treating OS.

Lactoferrin-Modified Gambogic Acid Liposomes for Colorectal Cancer Treatment.

Colorectal cancer (CRC) therapy is a big challenge, and seeking an effective and safe drug is a pressing clinical need. Gambogic acid is a potent antineoplastic agent without the drawback of bone marrow suppression. To improve its druggability (e.g., poor water solubility and tumor delivery), a lactoferrin-modified gambogic acid liposomal delivery system (LF-lipo) was developed to enhance the treatment efficacy of CRC. The LF-lipo can specifically bind LRP-1 expressed on colorectal cancer cells to enhance drug delivery to the tumor cells and yield enhanced therapeutic efficacy. The LF-lipo promoted tumor cell apoptosis and autophagy, reduced reactive oxygen species (ROS) levels in tumor cells, and inhibited angiogenesis; moreover, it could also repolarize tumor-associated macrophages from the M2 to M1 phenotype and induce ICD to activate T cells, exhibiting the capability of remodeling the tumor immune microenvironment. The liposomal formulation yielded an efficient and safe treatment outcome and has potential for clinical translation.

Temozolomide and chloroquine co-loaded mesoporous silica nanoparticles are effective against glioma

The past decades have witnessed great progress in nanoparticle‐based cancer‐targeting drug delivery systems, but their therapeutic potentials is yet to be fully exploited. In this research, temozolomide (TMZ) and chloroquine (CQ) were loaded into the mesoporous silica nanoparticles (MSNs), the surface was coated with polydopamine (PDA), and the complex was coupled with arginine-glycine-aspartic (RGD) to successfully prepare TMZ/CQ@MSN-RGD. RGD-MSNs accumulated more in the cell and tumor models than in unmodified MSNs in the in vitro and in vivo experiments and can directly induce apoptosis and autophagy in tumor cells. In addition, TMZ/CQ@MSN-RGD therapy enhanced the apoptosis effect of the RGD-MSNs in glioma. Therefore, the combination of autophagy inhibitor with chemotherapy drugs in nanocarriers may promote therapeutic efficacy in treating glioma.

Propranolol-induced autophagic dysfunction combined with a targeted metal-organic framework as a novel strategy for improving antitumor therapeutic efficacy

Autophagy is an intracellular biological process that involves capturing and degrading intracellular components to sustain metabolism and homeostasis. Especially in the late stage of tumorigenesis, autophagy contributes to the survival and growth of the tumors and promotes the aggressiveness of the tumors by facilitating metastasis. The overactivation of autophagy is also one of the important reasons for the drug resistance of the tumor. Nanoparticles (NPs) can induce autophagic process via certain components and morphologies, providing a new perspective for establishing tumor therapy strategies. Here, we report the preparation of targeted nanoparticles (NPs) encapsulated with paclitaxel (PTX) and propranolol (PRN) into poly(ethylene glycol) (PEG)-mediated zeolitic imidazolate framework-8 NPs to reverse the adverse effects of autophagy, where PEG improves the stability and dispersity of ZIF-8 NPs. PTX and Zn2+ released from the ZIF-8 NPs induce autophagy which could promote the survival of tumors. Propranolol (PRN), as a novel safe potential chemo-sensitizer, can act like a “valve” to block the fusion of autophagosome and lysosomes, and autolysosome degradation. The combinational application of PRN results in a boost of autophagosomes which directly suppresses the delivery of nutrients for tumor cells and changes the pro-survival mechanism of autophagy which promotes the cell-killing effect. In addition, these nanoparticles could cause an increase in intracellular ROS levels significantly and further induce apoptosis and autophagy of tumor cells. As a result, PTX&PRN@ZIF-8@HA NPs provide a novel potential method for the delivery of multiple therapeutics to convert the pro-survival effect of autophagy into a pro-death effect and offer the possibility of propranolol as a specific autophagy inhibitor for the tumor therapy.

Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1

BackgroundGreat progress has been made in applying immunotherapy to the clinical treatment of tumors. However, many patients with triple-negative breast cancer (TNBC) cannot benefit from immunotherapy due to the immune desert type of TNBC, which is unresponsive to immunotherapy. DMKG, a cell-permeable derivative of α-KG, has shown potential to address this issue.MethodWe investigated the effects of combining DMKG with radioimmunotherapy on TNBC. We assessed the ability of DMKG to promote tumor cell apoptosis and immunogenic death induced by radiotherapy (RT), as well as its impact on autophagy reduction, antigen and inflammatory factor release, DC cell activation, and infiltration of immune cells in the tumor area.ResultOur findings indicated that DMKG significantly promoted tumor cell apoptosis and immunogenic death induced by RT. DMKG also significantly reduced autophagy in tumor cells, resulting in increased release of antigens and inflammatory factors, thereby activating DC cells. Furthermore, DMKG promoted infiltration of CD8 + T cells in the tumor area and reduced the composition of T-regulatory cells after RT, reshaping the tumor immune microenvironment. Both DMKG and RT increased the expression of PD-L1 at immune checkpoints. When combined with anti-PD-L1 drugs (α-PD-L1), they significantly inhibited tumor growth without causing obvious side effects during treatment.ConclusionOur study underscores the potential of pairing DMKG with radioimmunotherapy as an effective strategy for treating TNBC by promoting apoptosis, immunogenic death, and remodeling the tumor immune microenvironment. This combination therapy could offer a promising therapeutic avenue for TNBC patients unresponsive to conventional immunotherapy.Graphical

Lower dose of metformin combined with artesunate induced autophagy-dependent apoptosis of glioblastoma by activating ROS-AMPK-mTOR axis

Glioblastoma multiform (GBM), one of the most common, aggressive primary brain tumours, demonstrates resistance to radiotherapy and chemotherapy after surgical resection and treatment failure. Metformin (MET) has been shown to suppress the proliferative capacity and invasion ability of GBM cells by activating AMPK and inhibiting mTOR, but the effective dose exceeded the maximum tolerated dose. Artesunate (ART) can exert certain anti-tumour effects by activating the AMPK-mTOR axis and inducing autophagy in tumour cells. Therefore, this study investigated the effects of MET combined with ART combination therapy on autophagy and apoptosis in GBM cells. MET combined with ART treatment effectively suppressed the viability, mono-cloning ability, migration and invasion capacities, as well as metastatic ability of GBM cells. The underlying mechanism involved modulation of the ROS-AMPK-mTOR axis, which was confirmed using 3-methyladenine and rapamycin to inhibit or promote the effects of MET combined with ART, respectively. The study findings suggest that MET used in combination with ART can induce autophagy-dependent apoptosis in GBM cells by activating the ROS-AMPK-mTOR pathway, providing a potential new treatment for GBM.

Lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer.

The International Agency for Research on Cancer determined that obesity is the primary preventable cause of breast cancer. The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) binds inflammatory mediators in obesity and its expression is reduced in human breast cancer. We created a new model to better understand how the obese microenvironment alters nuclear receptor function in breast cancer. The obesity related cancer phenotype was PPARγ dependent; deletion of PPARγ in mammary epithelium which is a tumor suppressor in lean mice unexpectedly increased tumor latency, reduced the luminal progenitor (LP) tumor cell fraction, and increased autophagic and senescent cells. Loss of PPARγ expression in mammary epithelium of obese mice increased expression of 2-aminoadipate semialdehyde synthase (AASS) which regulates lysine catabolism to acetoacetate. PPARγ-associated co-repressors and activators regulated AASS expression via a canonical response element. AASS expression was significantly reduced in human breast cancer, and AASS overexpression or acetoacetate treatment inhibited proliferation and induced autophagy and senescence in human breast cancer cell lines. Genetic or pharmacologic HDAC inhibition promoted autophagy and senescence in mammary tumor cells in vitro and in vivo. We concluded that lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer.

The application of cannabidiol in the treatment of glioblastoma

Glioblastoma multiforme (GBM), a high-grade astrocytoma, is an incurable brain tumor associated with genetic heterogeneity and dysregulated signaling pathways. As alternations of the endocannabinoid system have been demonstrated in GBM cells, the substances affecting its key elements may potentially inhibit tumor progression. Preclinical models indicate that CBD inhibits GBM tumor growth by inhibiting cellular proliferation, migration, and invasion but also promotes autophagy and apoptosis of tumor cells. Moreover, clinical trials indicate the safety and positive results regarding the survival of GBM patients upon cannabinoids treatment. Nevertheless, more human clinical trials with large sample sizes are urgently needed to implement cannabinoids, including CBD, into standard GBM treatment.

Arsenic Inhibits Proliferation and Induces Autophagy of Tumor Cells in Pleural Effusion of Patients with Non-Small Cell Lung Cancer Expressing EGFR with or without Mutations via PI3K/AKT/mTOR Pathway.

To clarify whether arsenic could exert inhibitory effects on tumor cells in pleural effusions of patients with non-small cell lung cancer (NSCLC), 36 NSCLC pleural effusion samples were collected from Changzheng Hospital and Ruijin Hospital, from 2019 to 2022. The genotype of epidermal growth factor receptor (EGFR) was identified. Tumor cells were isolated and treated with arsenic trioxide (ATO) or/and gefitinib. Additionally, six patients were intrapleurally administrated with ATO. Results showed that 25 samples bore EGFR wild type (WT) and 11 harbored EGFR mutations, including 6 with L858R, 3 with ΔE746-A750, and 2 with T790M. ATO diminished the number of tumor cells from patients with WT and mutant EGFR, down-regulated the expression or phosphorylation of EGFR, pmTOR, PI3K, PTEN, and p4E-BP1, and up-regulated the expression of LC3. Immunofluorescent experiments showed that ATO enhanced LC3 and P62. By contrast, gefitinib was only effective in those harboring EGFR sensitizing mutations. Notably, in patients with intrapleural ATO injection, the pleural effusion underwent a bloody to pale yellow color change, the volume of the pleural effusion was reduced, and the number of the tumor cells was significantly reduced. In conclusion, arsenic is effective against NSCLC with various EGFR genotypes in vitro and in vivo, and potentially circumvents gefitinib resistance.

Relationship Between Autophagy and Drug Resistance in Tumors.

Multidrug Resistance (MDR) in tumor cells, a phenomenon in which tumor cells become resistant to chemotherapeutic drugs with different chemical structures and mechanisms of action, is a major obstacle to tumor therapy and is an urgent problem to be addressed. Autophagy, widely found in eukaryotic cells, is a lysosome-dependent pathway of self-degradation. In different environments, autophagy can play different roles in the self-protection of cells. At different stages of tumorigenesis, autophagy can play two distinct roles: inhibition of cancer and promotion of cancer. The relationship between autophagy and drug resistance in tumor cells is complex. Moreover, autophagy can play a role in promoting drug resistance and drug sensitivity through different molecular pathways. This study aimed to investigate the relationship between autophagy and drug resistance in tumor cells from the perspective of molecular mechanisms.