Doxorubicin Resistance Research Articles

Drug-induced self-assembled nanovesicles for doxorubicin resistance reversal via autophagy inhibition and delivery synchronism.

Background: As a classical autophagy inhibitor, CQ has been supposed to increase the sensitivity of tumors to chemotherapeutics. However, there exists a quite huge gap between laboratory research and clinical application, which is related to the distinct pharmacokinetic behavior of CQ to a great extent.Methods: Based on amphiphilic copolymer PPAP, a pH-responsive drug-induced self-assembled nanovesicle, named DC-DIV/C, was constructed to load DOX⋅HCl and CQ. The physicochemical properties of DC-DIV/C were characterized. To validate the cooperative action and delivery synchronism of DOX⋅HCl and CQ, cytotoxicity, apoptosis, cellular uptake and autophagy assay were investigated in DOX⋅HCl resistant cancer cells. The pharmacokinetic character and antitumor effect of DC-DIV/C were evaluated on rats and nude mice bearing xenograft drug-resistant K562/ADR tumors, respectively.Results: DC-DIV/C could simultaneously encapsulate DOX·HCl and CQ at the optimal ratio of 1:2. In vitro and in vivo tests confirmed that DC-DIV/C acted as an excellent vehicle for the synchronous delivery of DOX⋅HCl and CQ during the process of blood circulation, cellular uptake and intracellular release. Furthermore, CQ accomplished autophagy inhibition to reduce the IC50 of DOX⋅HCl resistant cancer cells. Consequently, DC-DIV/C exhibited the extremely improved anti-tumor effect with 84.52% TIR on K562/ADR tumor.Conclusion: This study provides a promising and powerful strategy to achieve enhanced treatment outcomes for the precise combination therapy.

Using MicroRNA expression levels to detect doxorubicin resistance in breast cancer: A systematic review

Using MicroRNA expression levels to detect doxorubicin resistance in breast cancer: A systematic review

KCa1.1 K+ Channel Inhibition Overcomes Resistance to Antiandrogens and Doxorubicin in a Human Prostate Cancer LNCaP Spheroid Model.

Several types of K+ channels play crucial roles in tumorigenicity, stemness, invasiveness, and drug resistance in cancer. Spheroid formation of human prostate cancer (PC) LNCaP cells with ultra-low attachment surface cultureware induced the up-regulation of cancer stem cell markers, such as NANOG, and decreased the protein degradation of the Ca2+-activated K+ channel KCa1.1 by down-regulating the E3 ubiquitin ligase, FBXW7, compared with LNCaP monolayers. Accordingly, KCa1.1 activator-induced hyperpolarizing responses were larger in isolated cells from LNCaP spheroids. The pharmacological inhibition of KCa1.1 overcame the resistance of LNCaP spheroids to antiandrogens and doxorubicin (DOX). The protein expression of androgen receptors (AR) was significantly decreased by LNCaP spheroid formation and reversed by KCa1.1 inhibition. The pharmacological and genetic inhibition of MDM2, which may be related to AR protein degradation in PC stem cells, revealed that MDM2 was responsible for the acquisition of antiandrogen resistance in LNCaP spheroids, which was overcome by KCa1.1 inhibition. Furthermore, a member of the multidrug resistance-associated protein subfamily of ABC transporters, MRP5 was responsible for the acquisition of DOX resistance in LNCaP spheroids, which was also overcome by KCa1.1 inhibition. Collectively, the present results suggest the potential of KCa1.1 in LNCaP spheroids, which mimic PC stem cells, as a therapeutic target for overcoming antiandrogen- and DOX-resistance in PC cells.

Dependence of ABCB1 transporter expression and function on distinct sphingolipids generated by ceramide synthases-2 and -6 in chemoresistant renal cancer

Oncogenic multidrug resistance is commonly intrinsic to renal cancer based on the physiological expression of detoxification transporters, particularly ABCB1, thus hampering chemotherapy. ABCB1 activity is directly dependent on its lipid microenvironment, localizing to cholesterol- and sphingomyelin (SM)-rich domains. As ceramides are the sole source for SMs, we hypothesized that ceramide synthase (CerS)-derived ceramides regulate ABCB1 activity. Using data from RNA-Seq databases, we found that patient kidney tumors exhibited increased CerS2 mRNA, which was inversely correlated with CerS6 mRNA in ABCB1+ clear cell carcinomas. Endogenous elevated CerS2 and lower CerS5/6 mRNA and protein resulted in disproportionately higher CerS2 to CerS5/6 activities (approximately twofold) in chemoresistant ABCB1high (A498, Caki-1) compared with chemosensitive ABCB1low (ACHN, normal human proximal convoluted tubule cell) cells. In addition, lipidomics analyses by HPLC–MS/MS showed bias toward CerS2-associated C20:0/C20:1-ceramides compared with CerS5/6-associated C14:0/C16:0-ceramides (2:1). SMs were similarly altered. We demonstrated that chemoresistance to doxorubicin in ABCB1high cells was partially reversed by inhibitors of de novo ceramide synthesis (l-cycloserine) and CerS (fumonisin B1) in cell viability assays. Downregulation of CerS2/6, but not CerS5, attenuated ABCB1 mRNA, protein, plasma membrane localization, rhodamine 123+ efflux transport activity, and doxorubicin resistance. Similar findings were observed with catalytically inactive CerS6-H212A. Furthermore, CerS6-targeting siRNA shifted ceramide and SM composition to ultra long-chain species (C22–C26). Inhibitors of endoplasmic reticulum–associated degradation (eeyarestatin I) and the proteasome (MG132, bortezomib) prevented ABCB1 loss induced by CerS2/6 downregulation. We conclude that a critical balance in ceramide/SM species is prerequisite to ABCB1 expression and functionalization, which could be targeted to reverse multidrug resistance in renal cancers.

Adaptor SH3BGRL drives autophagy-mediated chemoresistance through promoting PIK3C3 translation and ATG12 stability in breast cancers

ABSTRACT Acquired chemotherapy resistance is one of the main culprits in the relapse of breast cancer. But the underlying mechanism of chemotherapy resistance remains elusive. Here, we demonstrate that a small adaptor protein, SH3BGRL, is not only elevated in the majority of breast cancer patients but also has relevance with the relapse and poor prognosis of breast cancer patients. Functionally, SH3BGRL upregulation enhances the chemoresistance of breast cancer cells to the first-line doxorubicin treatment through macroautophagic/autophagic protection. Mechanistically, SH3BGRL can unexpectedly bind to ribosomal subunits to enhance PIK3C3 translation efficiency and sustain ATG12 stability. Therefore, inhibition of autophagy or silence of PIK3C3 or ATG12 can effectively block the driving effect of SH3BGRL on doxorubicin resistance of breast cancer cells in vitro and in vivo. We also validate that SH3BGRL expression is positively correlated with that of PIK3C3 or ATG12, as well as the constitutive occurrence of autophagy in clinical breast cancer tissues. Taken together, our data reveal that SH3BGRL upregulation would be a key driver to the acquired chemotherapy resistance through autophagy enhancement in breast cancer while targeting SH3BGRL could be a potential therapeutic strategy against breast cancer.

Repositioning application of polyoxyethylene (20) sorbitan monooleate on ocular drug resistance and cancer multi-drug resistance by inhibiting the ATPase activity of human multidrug resistance protein 1 and P-glycoprotein

Drug efflux transporters were highly related to the clinical drug resistance issues, such as cancer multi-drug resistance (MDR) and ocular drug resistance. In the present study, with the focus on human multi-drug resistance protein 1 (MRP1) and P-glycoprotein (P-gp), the inhibitory kinetics of polyoxyethylene (20) sorbitan monooleate (Tween 80) on both drug binding sites and ATPase were in-depth evaluated. We used the stable-cloned ABCB1/Flp-In™-293 and ABCC1/Flp-In™-293 cell lines, and inside-out membrane vesicles for underlying mechanisms investigation while used the drug induced cancer MDR cell line KB/VIN and human retinal pigmented epithelium cell line ARPE-19 for efficacy evaluation. Results showed that Tween 80 exhibited non-competitive inhibition on the doxorubicin efflux of P-gp and MRP1, with the inhibitory affinity 0.00195% (14.89 μM) and 0.00245% (18.7 μM), respectively. Tween 80 inhibited the basal ATPase activity of P-gp and MRP1 in a dose-dependent manner (0.0002–0.02%) and demonstrated significant reversing effects on the doxorubicin, paclitaxel, and vincristine resistance at the concentration of 0.001% (7.63 μM). This was the first thorough study revealing the interactions between Tween 80 and P-gp or MRP1 at a molecular level and these findings suggested that Tween 80 was a potential candidate for future combinatorial regimens applied in the “drug resistance” issue.

Stimuli-responsive, dual-function prodrug encapsulated in hyaluronic acid micelles to overcome doxorubicin resistance

Multidrug resistance (MDR) is the main challenge faced by cancer chemotherapy. Drug-conjugate offers a promising strategy for breast cancer therapy. In this regard, we developed a DNVM multifunctional drug delivery system by crosslinking doxorubicin (DOX) and vitamin E succinate (VES) with a pH-sensitive hydrazone bond and then encapsulated the DOX-NN-VES prodrug into pH-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) micelles. DOX resistant MCF-7/ADR cell were adopted as a model to study the capability and mechanism of MDR reversal. DNVM exhibited much higher cytotoxicity and cell uptake efficiency compared with that of acid-insensitive DOX-VES loaded HOD micelles (DVSM) and DOX loaded HOD micelles (DOXM), indicating the better capacity of DNVM for the reversal of MDR. Moreover, DNVM prevented drug efflux more effectively, inhibited the expression of P-gp, induced excessive production of reactive oxygen species and affected the expression of apoptosis-related proteins. In vivo experiments showed that DNVM significantly inhibited the tumor growth with no obvious changes in the body weight of MCF-7/ADR cells-bearing nude mice. The results suggested that the “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for DOX resistant tumor cells and has the potential to overcome tumor MDR. Statement of SignificanceA dual-functional pH-sensitive doxorubicin - vitamin E succinate prodrug was developed and loaded into tumor microenvironment-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine micelle system (DNVM) for sequencing stimuli-release and overcoming doxorubicin resistance. The “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for doxorubicin resistant tumor cells and has the potential to overcome tumor multiple drug resistance.

Gene Network Analysis of Hepatocellular Carcinoma Identifies Modules Associated with Disease Progression, Survival, and Chemo Drug Resistance.

BackgroundHepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. HCC transcriptome has been extensively studied; however, the progress in disease mechanisms, prognosis, and treatment is still slow.MethodsA rank-based module-centric workflow was introduced to analyze important modules associated with HCC development, prognosis, and drug resistance. The currently largest HCC cell line RNA-Seq dataset from the LIMORE database was used to construct the reference modules by weighted gene co-expression network analysis.ResultsThirteen reference modules were identified with validated reproducibility. These modules were all associated with specific biological functions. Differentially expressed module analysis revealed the crucial modules during HCC development. Modules and hub genes are indicative of patient survival. Modules can differentiate patients in different HCC stages. Furthermore, drug resistance was revealed by drug-module association analysis. Based on differentially expressed modules and hub genes, six candidate drugs were screened. The hub genes of those modules merit further investigation.ConclusionWe proposed a reference module-based analysis of the HCC transcriptome. The identified modules are associated with HCC development, survival, and drug resistance. M3 and M6 may play important roles during HCV to HCC development. M1, M3, M5, and M7 are associated with HCC survival. High M4, high M9, low M1, and low M3 may be associated with dasatinib, doxorubicin, CD532, and simvastatin resistance. Our analysis provides useful information for HCC diagnosis and treatment.

CircATXN7 contributes to the progression and doxorubicin resistance of breast cancer via modulating miR-149-5p/HOXA11 pathway.

Breast cancer is a frequent tumor threatening the health of women. Circular RNAs (circRNAs) play vital roles in cancer progression and chemoresistance. Herein, we mainly investigate the role and potential mechanism of circRNA ataxin 7 (circATXN7; circ_0066436) in breast cancer. RNA expression levels were detected via quantitative real-time PCR (qPCR), western blot and immunohistochemistry. Cell viability and half inhibitory concentration (IC50) of doxorubicin were assessed by cell counting kit-8 (CCK-8) method. Cell proliferation, migration and invasion were determined by CCK-8, 5-ethynyl-2'-deoxyuridine, colony formation and transwell assays. The binding relationship between microRNA-149-5p (miR-149-5p) and circATXN7 or homeobox A11 (HOXA11) was validated via dual-luciferase reporter assay and RNA immunoprecipitation assay. Xenograft assay was conducted to analyze the effect of circATXN7 on doxorubicin resistance of breast cancer. CircATXN7 and HOXA11 levels were enhanced, whereas miR-149-5p level was declined in breast cancer tissues and cells. CircATXN7 silencing suppressed breast cancer development and doxorubicin resistance. Additionally, circATXN7 upregulated HOXA11 via absorbing miR-149-5p, thereby inducing breast cancer cell progression and reducing doxorubicin sensitivity. Besides, depletion of circATXN7 enhanced doxorubicin sensitivity in vivo. Interference of circATXN7 inhibited breast cancer progression and doxorubicin resistance via mediating miR-149-5p/HOXA11 axis, which might provide a possible biomarker for breast cancer therapy.

Dysregulated MDR1 by PRDM1/Blimp1 Is Involved in the Doxorubicin Resistance of Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

Introduction: The chemoresistance mechanism of diffuse large B-cell lymphoma (DLBCL) is still poorly understood, and patient prognosis remains unsatisfactory. This study aimed to investigate drug resistance mechanisms in non-germinal center B-cell-like (non-GCB) DLBCL. Methods: Doxorubicin (DOX)-resistant OCI-Ly3 cells were generated through long-term incubation of cells in a medium with gradually increasing DOX concentrations. The expression levels of genes related to drug metabolism were determined using a functional gene grouping polymerase chain reaction (PCR) array. Drug-resistant proteins were identified using bioinformatics, and molecular association networks were subsequently generated. The association and mechanism of key genes were determined using a dual-luciferase reporter assay System and chromatin immunoprecipitation (ChIP). The expression of drug-resistant genes and target genes was then measured using Western blotting and immunohistochemistry. The correlation between gene expressions was analyzed using Spearman’s rank correlation coefficient. Results: Using the PCR array, MDR1 was identified as the key gene that regulates DOX resistance in OCI-Ly3/DOX-A100, a non-GCB DLBCL cell line. The dual-luciferase reporter assay system demonstrated that MDR1 transcription could be inhibited by PRDM1. ChIP results showed that PRDM1 had the ability to bind to the promoter region (−1,132 to −996) of MDR1. In OCI-Ly3/DOX cells, NF-κB activity and PRDM1 expression decreased with an increase in drug-resistant index, whereas MDR1 expression increased with enhanced drug resistance. Immunohistochemical analysis revealed that relative MDR1 expression was higher than that of PRDM1 in human DLBCL tissue samples. A negative correlation was observed between MDR1 and PRDM1. Conclusion: In non-GCB DLBCL cells, NF-κB downregulates PRDM1 and thereby promotes MDR1 transcription by terminating PRDM1-induced transcriptional inhibition of MDR1. Such a mechanism may explain the reason for disease recurrence in non-GCB DLBCL after R-CHOP or combined CHOP with bortezomib treatment. Our findings may provide a potential therapeutic strategy for reducing drug resistance in patients with DLBCL.

The matricellular protein CCN6 differentially regulates mitochondrial metabolism in normal epithelium and in metaplastic breast carcinomas.

Metaplastic breast carcinoma (MBC) is an aggressive subtype of triple negative breast cancer with undefined precursors, limited response to chemotherapy, and frequent distant metastasis. Our laboratory has reported that CCN6/WISP3, a secreted protein that regulates growth factor signaling, is downregulated in over 85% of MBCs. Through generation of a mammary epithelial cell-specific Ccn6 knockout mouse model (MMTV-cre;Ccn6fl/fl) we have demonstrated that CCN6 is a tumor suppressor for MBC; MMTV-cre;Ccn6fl/fl mice develop tumors recapitulating the histopathology and proteogenomic landscape of human MBC, but the mechanisms need further investigation. In this study, we report that preneoplastic mammary glands of 8-week-old MMTV-Cre;Ccn6fl/fl female mice show significant downregulation of mitochondrial respiratory chain genes compared to controls, which are further downregulated in MBCs of MMTV-Cre;Ccn6fl/fl mice and humans. We found that CCN6 downregulation in non-tumorigenic breast cells reduces mitochondrial respiration and increases resistance to stress-induced apoptosis compared to controls. Intracellular ectopic CCN6 protein localizes to the mitochondria in MDA-MB-231 mesenchymal-like breast cancer cells, increases mitochondrial respiration and generation of reactive oxygen species, and reverses doxorubicin resistance of MBC cells. Our data highlight a novel function of CCN6 in the regulation of redox states in preneoplastic progression and suggest potential preventative and treatment strategies against MBC based on CCN6 upregulation.

PiR-39980 mediates doxorubicin resistance in fibrosarcoma by regulating drug accumulation and DNA repair

Resistance to doxorubicin (DOX) is an obstacle to successful sarcoma treatment and a cause of tumor relapse, with the underlying molecular mechanism still unknown. PIWI-interacting RNAs (piRNAs) have been shown to enhance patient outcomes in cancers. However, there are few or no reports on piRNAs affecting chemotherapy in cancers, including fibrosarcoma. The current study aims to investigate the relationship between piR-39980 and DOX resistance and the underlying mechanisms. We reveal that piR-39980 is less expressed in DOX-resistant HT1080 (HT1080/DOX) fibrosarcoma cells. Our results show that inhibition of piR-39980 in parental HT1080 cells induces DOX resistance by attenuating intracellular DOX accumulation, DOX-induced apoptosis, and anti-proliferative effects. Its overexpression in HT1080/DOX cells, on the other hand, increases DOX sensitivity by promoting intracellular DOX accumulation, DNA damage, and apoptosis. The dual-luciferase reporter assay indicates that piR-39980 negatively regulates RRM2 and CYP1A2 via direct binding to their 3′UTRs. Furthermore, overexpressing RRM2 induces DOX resistance of HT1080 cells by rescuing DOX-induced DNA damage by promoting DNA repair, whereas CYP1A2 confers resistance by decreasing intracellular DOX accumulation, which piR-39980 restores. This study reveals that piR-39980 could reduce fibrosarcoma resistance to DOX by modulating RRM2 and CYP1A2, implying that piRNA can be used in combination with DOX.

Exosomal transfer of circ_0006174 contributes to the chemoresistance of doxorubicin in colorectal cancer by depending on the miR-1205/CCND2 axis.

Exosomes are the mediators of intercellular signal transduction, and they have been involved in the carcinogenesis and chemoresistance of tumor cells. Herein, we intended to investigate whether circular RNA (circRNA) circ_0006174 can regulate chemoresistance of doxorubicin (DOX) in colorectal cancer via exosomes. Forty-one pairs of normal and CRC (DOX sensitive, n = 16; DOX resistant, n = 25) samples were collected. The resistant cell lines (LoVo/DOX and HCT116/DOX) were constructed by exposure of parental cell lines (LoVo and HCT116) to DOX. The detection of circ_0006174, microRNA-1205 (miR-1205), and cyclin D2 (CCND2) was performed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8(CCK-8) was applied for determining the half of inhibitory concentration (IC50) of DOX and cell proliferation. The migration and invasion capacities were analyzed via transwell assay. Exosomes were extracted using ultracentrifugation. Protein levels were determined using western blot. Dual-luciferase reporter assay was used for affirming target interaction. In vivo experiment was performed by establishing xenograft models in mice. Circ_0006174 level was upregulated in DOX-resistant CRC tissues and cells. The downregulation of circ_0006174 inhibited DOX resistance, cell proliferation, migration, and invasion in DOX-resistant CRC cells. Interestingly, the abundant circ_0006174 was enriched in exosomes derived from DOX-resistant CRC cells. Furthermore, circ_0006174 could enhance DOX resistance via the exosomal intercellular transfer. Moreover, we validated the target relation of circ_0006174/miR-1205 or miR-1205/CCND2. The effect of exosomal circ_0006174 on DOX resistance was achieved by upregulating the miR-1205-mediated CCND2. In vivo, knockdown of circ_0006174 also enhanced tumor sensitivity to DOX by targeting miR-1205/CCND2 axis. Altogether, these findings unraveled that circ_0006174-enriched exosomes elevated DOX chemoresistance in CRC by the miR-1205/CCND2 axis. The exosomal circ_0006174 can be used as an available biomarker for the diagnosis of chemoresistance in CRC.

Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling.

Emerging evidence suggests that breast cancer stem cells (BCSCs), and epithelial–mesenchymal transition (EMT) may be involved in resistance to doxorubicin. However, it is unlear whether the doxorubicin-induced EMT and expansion of BCSCs is related to cancer dormancy, or outgrowing cancer cells with maintaining resistance to doxorubicin, or whether the phenotypes can be transferred to other doxorubicin-sensitive cells. Here, we characterized the phenotype of doxorubicin-resistant TNBC cells while monitoring the EMT process and expansion of CSCs during the establishment of doxorubicin-resistant MDA-MB-231 human breast cancer cells (DRM cells). In addition, we assessed the potential signaling associated with the EMT process and expansion of CSCs in doxorubicin-resistance of DRM cells. DRM cells exhibited morphological changes from spindle-shaped MDA-MB-231 cells into round-shaped giant cells. They exhibited highly proliferative, EMT, adhesive, and invasive phenotypes. Molecularly, they showed up-regulation of Cyclin D1, mesenchymal markers (β-catenin, and N-cadherin), MMP-2, MMP-9, ICAM-1 and down-regulation of E-cadherin. As the molecular mechanisms responsible for the resistance to doxorubicin, up-regulation of EGFR and its downstream signaling, were suggested. AKT and ERK1/2 expression were also increased in DRM cells with the advancement of resistance to doxorubicin. Furthermore, doxorubicin resistance of DRM cells can be transferred by autocrine signaling. In conclusion, DRM cells harbored EMT features with CSC properties possessing increased proliferation, invasion, migration, and adhesion ability. The doxorubicin resistance, and doxorubicin-induced EMT and CSC properties of DRM cells, can be transferred to parental cells through autocrine signaling. Lastly, this feature of DRM cells might be associated with the up-regulation of EGFR.

Glabratephrin reverses doxorubicin resistance in triple negative breast cancer by inhibiting P-glycoprotein

Triple-negative breast cancer is one of the most aggressive breast cancer. The first therapeutic option is chemotherapy, often based on anthracycline as doxorubicin. However, chemotherapy efficacy is limited in by the presence of P-glycoprotein (Pgp), a membrane transporter protein that effluxes doxorubicin, reducing its cellular accumulation and toxicity. Inhibiting Pgp activity with effective and non-toxic products is still an open challenge. In this work, we demonstrated that the natural product Glabratephrin (Glab), a prenylated flavonoid from Tephrosia purpurea with a unique chemical structure, increased doxorubicin accumulation and cytotoxicity in triple negative breast cancer cells with high levels of Pgp, characterized by both acquired or intrinsic resistance to doxorubicin. Glab also reduced the growth of Pgp-expressing tumors, without adding significant extra-toxicities to doxorubicin treatment. Interestingly, Glab did not change the expression of Pgp, but it reduced the affinity for Pgp and the efflux of doxorubicin, as suggested by the increased Km and the reduced Vmax. In silico molecular docking predicted that Glab binds two residues (phenylalanine 322, glutamine 721) localized in the transmembrane domains of Pgp, facing the extracellular environment. Moreover, site-directed mutagenesis identified glycine 185 as a critical residue mediating the reduced catalytic efficacy of Pgp elicited by Glab. We propose Glab as an effective and safe compound able to reverse doxorubicin resistance mediated by Pgp in triple negative breast cancers, opening the way to a new combinatorial approach that may improve chemotherapy efficacy in the most refractory and aggressive breast cancer.

The Long Non-Coding RNA SAMMSON Is a Regulator of Chemosensitivity and Metabolic Orientation in MCF-7 Doxorubicin-Resistant Breast Cancer Cells.

Simple SummaryBreast cancer is the most common cancer in women, representing about one third of cancers in developed countries. Despite recent advances in diagnostic methods and increasingly early detection, breast cancer recurrence occurs in more than 20% of patients. Chemoresistance represents an important cause of this recurrence, but the mechanisms involved in this phenomenon, are still largely unknown. One feature of chemoresistant cancer cells is the reorientation of the energetic metabolism to sustain cell proliferation. Recently, long non-coding RNAs (lncRNAs) have emerged as important regulators of cellular metabolic orientation. In the present work, we gave special attention to the long non-coding RNA SAMMSON and addressed the role of this lncRNA in metabolic orientation and chemoresistance of doxorubicin-resistant breast cancer cells. The results shed light on the possible modulation of the SAMMSON expression as an innovative therapeutic approach to target chemoresistant cancer cells specifically.Despite improvements in therapeutic strategies for treating breast cancers, tumor relapse and chemoresistance remain major issues in patient outcomes. Indeed, cancer cells display a metabolic plasticity allowing a quick adaptation to the tumoral microenvironment and to cellular stresses induced by chemotherapy. Recently, long non-coding RNA molecules (lncRNAs) have emerged as important regulators of cellular metabolic orientation. In the present study, we addressed the role of the long non-coding RNA molecule (lncRNA) SAMMSON on the metabolic reprogramming and chemoresistance of MCF-7 breast cancer cells resistant to doxorubicin (MCF-7dox). Our results showed an overexpression of SAMMSON in MCF-7dox compared to doxorubicin-sensitive cells (MCF-7). Silencing of SAMMSON expression by siRNA in MCF-7dox cells resulted in a metabolic rewiring with improvement of oxidative metabolism, decreased mitochondrial ROS production, increased mitochondrial replication, transcription and translation and an attenuation of chemoresistance. These results highlight the role of SAMMSON in the metabolic adaptations leading to the development of chemoresistance in breast cancer cells. Thus, targeting SAMMSON expression levels represents a promising therapeutic route to circumvent doxorubicin resistance in breast cancers.

Mitochondrial temperature-responsive drug delivery reverses drug resistance in lung cancer

Reversal of cancer drug resistance remains a critical challenge in chemotherapy. Mitochondria-targeted drug delivery has been suggested to mitigate drug resistance in cancer. To overcome the intrinsic limitations in conventional mitochondrial targeting strategies, we develop mitochondrial temperature-responsive drug delivery to reverse doxorubicin (DOX) resistance in lung cancer. Results demonstrate that the thermoresponsive nanocarrier can prevent DOX efflux and facilitate DOX accumulation and mitochondrial targeting in DOX-resistant tumors. As a consequence, thermoresponsive nanocarrier enhances the cytotoxicity of DOX and reverses the drug resistance in tumor-bearing mice. This work represents the first example of mitochondrial temperature-responsive drug delivery for reversing cancer drug resistance.

N-Glycoproteomics Study of Putative N-Glycoprotein Biomarkers of Drug Resistance in MCF-7/ADR Cells.

The online version contains supplementary material available at 10.1007/s43657-021-00029-8.

HMGB1 Promotes Resistance to Doxorubicin in Human Hepatocellular Carcinoma Cells by Inducing Autophagy via the AMPK/mTOR Signaling Pathway.

Chemoresistance remains as a major hindrance in the treatment of hepatocellular carcinoma (HCC). High mobility group box protein 1 (HMGB1) enhances autophagic flux and protects tumor cells from apoptosis, which results in acquired drug resistance. However, the exact mechanisms underlying HMGB1-modulated autophagy in HCC chemoresistance remain to be defined. In the present study, we found that administration of doxorubicin (DOX) significantly promoted HMGB1 expression and induced HMGB1 cytoplasmic translocation in human HCC cell lines BEL7402 and SMMC7721, which enhanced autophagy that contributes to protecting HCC cells from apoptosis and increasing drug resistance. Moreover, we observed HMGB1 translocation and elevation of autophagy in DOX-resistant BEL7402 and SMMC7721 cells. Additionally, inhibition of HMGB1 and autophagy increased the sensitivities of BEL-7402 and SMMC-7721 cells to DOX and re-sensitized their DOX-resistant cells. Subsequently, we confirmed with HMGB1 regulated autophagy by activating the 5ʹ adenosine monophosphate-activated protein kinase (AMPK)/mTOR pathway. In summary, our results indicate that HMGB1 promotes acquired DOX resistance in DOX-treated BEL7402 and SMMC7721 cells by enhancing autophagy through the AMPK/mTOR signaling pathway. These findings provide the proof-of-concept that HMGB1 inhibitors might be an important targeted treatment strategy for HCC.

Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer

Drug resistance has become one of the largest challenges for cancer chemotherapies. Under certain conditions, cancer cells hijack autophagy to cope with therapeutic stress, which largely undermines the chemo-therapeutic efficacy. Currently, biomarkers indicative of autophagy-derived drug resistance remain largely inclusive. Here, we report a novel role of lipid rafts/cholesterol-enriched membrane micro-domains (CEMMs) in autophagosome biogenesis and doxorubicin resistance in breast tumors. We showed that CEMMs are required for the interaction of VAMP3 with syntaxin 6 (STX6, a cholesterol-binding SNARE protein). Upon disruption of CEMM, VAMP3 is released from STX6, resulting in the trafficking of ATG16L1-containing vesicles to recycling endosomes and subsequent autophagosome biogenesis. Furthermore, we found that CEMM marker CAV1 is decreased in breast cancer patients and that the CEMM deficiency-induced autophagy is related to doxorubicin resistance, which is overcome by autophagy inhibition. Taken together, we propose a novel model whereby CEMMs in recycling endosomes support the VAMP3 and STX6 interaction and function as barriers to limit the activity of VAMP3 in autophagic vesicle fusion, thus CEMM deficiency promotes autophagosome biogenesis and doxorubicin resistance in breast tumors.