With the advancement of next generation sequencing in past several years, a rising number of non-coding RNAs have been found as new actors to regulate gene expression. Non-coding RNAs not only play important roles in carcinogenesis, but also affect the clinical treatment strategies. They have been proved to be deeply correlated with chemoresistance in several cancers. Ovarian cancer is the leading cause of death in gynecological malignancy, with low 5-year survival rate. Most patients are identified when they have late-stage disease. This review mainly makes a compilation of the most relevant research literature in this field with the purpose of shedding light on the relation between ncRNAs and chemoresistance in ovarian cancer.

Using a breast cancer (BC) cellular model: MDA-MB-231 cells with blocked synthesis of galacto-sylceramide (GalCer; MDA.Δ.UGT8.4) and MCF7 and T47D cells that over-produced GalCer (MCF7.UGT8 and T47D.UGT8), we found that GalCer increased resistance to doxorubicin, paclitaxel, and cisplatin serving as an anti-apoptotic molecule. These results were supported by a study using murine mammary carcinoma 4T1 cells over-producing GalCer, which were trans-planted into Balb/c mice and were more resistant to doxorubicin therapy than the control. Sub-sequent studies revealed that GalCer specifically downregulated the level of pro-apoptotic TNFRSF1B and TNFRSF9 genes and increased the level of the anti-apoptotic BCL2 gene expres-sion, suggesting that GalCer regulates their expression at the level of transcription. Consistent with this hypothesis, MDA-MB-231 and MCF7.UGT8 cells with high GalCer content showed lower activity of TNFRSF1B and TNFRSF9 promoters than cells lacking GalCer. In contrast, the activity of the BCL2 promoter in MCF7.UGT8 was higher than in MCF7 cells without GalCer. However, no difference in BCL2 promoter activity was observed between MDA-MB-231 cells with high GalCer level and GalCer-negative MDA.Δ.UGT8.4 cells. Instead, we found that GalCer increased the stability of Bcl-2 mRNA. As a candidate protein that simultaneously increases the expression of TNFRSF1B and TNFRSF9 genes and decreases the expression of BCL2 gene and stability of Bcl-2 transcripts is probably p53, its expression was analysed in BC cells containing various amounts of GalCer. In agreement with this hypothesis, BC cells with high GalCer con-tent are characterized by significantly lower expression of p53, and inhibition of p53 using siR-NA resulted in decreased expression of TNFRS1B and TNFRS9 genes and increased expression of BCL2 gene.

Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multi-step nature of the process offers multiple regulation points prone to be deregulated and cause different human disease, but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within tumor microenvironment, but also to increase invasiveness and resistance to anti-cancer drugs such as chemotherapy. This review collects all clinical evidences of autophagy deregulation during cholangiocarcinogenesis together with all pre-clinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggests an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Pre-clinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer

There has been no significant efficacy in treatment for osteosarcoma (OS) metastasis after nearly four decades of trials. This motivates us to elucidate OS therapies according to their four bidirectional mutation stages. To refresh the OS therapy status quo, the historical developments and clinical advancements are briefly described. However, the main issue of metastasis remains unresolved, accounting for 90% of pulmonary metastasis deaths. Thus, this metastasis problem is related to immune evasion and chemoresistance that are being induced after long-term treatment by the use of immunotherapy for tumorigenesis. Therefore, it is rationale to discuss the relationship cycles of mutation stages including tumorigenesis, metastasis, immune evasion, and chemoresistance. Even though many combinational and targeted therapies have been developed to intensify these mutation treatments, successful clinical translations with higher cure rates are still rare. Through this review, an in-depth understanding of the bidirectional relationship between the four OS mutation stages and their respective therapies is provided. Herein, we summarise the medicines used to treat tumorigenesis, including COLGALT2 inhibitors, Tra2B, and AGAP1, miR-148a and miR-21-5p EVs, and the lncRNA LIFR-AS1. Following the medicines used to treat metastasis are AXL, miR-135a-5p, mRNA BCL6, TGFβ1, Tim-3, SOCS5, CASC15, KLF3-AS1, PDCD4, ATG5, and Rab22a-NeoF1. Then the medicines used to treat immune evasion are N-cadherin, anti-IL-9, USP12 inhibitor, IgG-4+ B-cells, LAP inhibitor, anti-Wnt2 mAb, anti-αvβ8 integrin, HK2-mediated IκBα, IDO inhibitor with NO, and TGF-βRII with anti-IgG1. Finally, the medicines used to treat chemoresistance are DHFR, FPGS, HSP-90AA1, XCT-790, ATKI, and IGF1. As a result, this contribution is expected to serve as a reference and guide for scientists and clinicians.

The efficacy of chemotherapy depends on sensitivity and intrinsic or acquired drug resistance of cancer cells. The n-3 long chain polyunsaturated fatty acids (n-3 LCPUFAs) are considered chemosensitizing agents and revertants of multidrug resistance by pleiotropic mechanisms. The specific mechanisms are not fully understood, but nowadays, it is widely accepted that there are a complex network of mechanisms, including alteration in gene expression, modulation of cellular proliferation and differentiation, induction of apoptosis, generation of reactive oxygen species and lipid peroxidation. A crucial mechanism in the control of cell drug uptake and efflux is related to n-3 LCPUFA influence on membrane lipid composition. The incorporation of docosahexaenoic acid in the lipid rafts produces significant changes in their physical-chemical properties affecting content and functions of transmembrane proteins, such as growth factors, receptors and ATP-binding cassette transporters. Of note, n-3 LCPUFAs often impact on the lipid compositions more in chemoresistant cells than in chemosensitive cells, suggesting their adjuvant role in cancer treatment.

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the “classical” protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage independent growth of etoposide resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide resistant RB cells, impacts mirroring PTPRE KD effects and indicating PTPRE regulation via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and - dependent on the cell line - also AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma.

Platinum-resistant high-grade serous ovarian cancer (HGSOC) is invariably a fatal disease, so a central goal in ovarian cancer research is to develop novel strategies to overcome platinum resistance. Treatment is thus moving towards personalized therapy. However, validated molecular biomarkers to predict patients’ risk of developing platinum resistance are still lacking. Extracellular vesicles (EVs) are promising candidates for biomarkers. EpCAM-specific EVs are largely unexplored biomarkers in predicting chemoresistance. Using transmission electron microscopy, nanoparticle tracking analysis and flow cytometry, we compared the characteristics of EVs released from a cell line derived from a clinically confirmed cisplatin-resistant patient (OAW28) and EVs released from two cell lines from tumors sensitive to platinum-based chemotherapy (PEO1, OAW42). We showed that characteristics of EVs released from the HGSOC cell line of chemoresistant patients had higher heterogeneity in size, a larger proportion of medium/large (>200nm) EVs and a higher number of released EpCAM-positive EVs of different sizes, although expression of EpCAM predominated, especially on those larger than 400 nm. We also determined a strong positive correlation between the concentration of EpCAM-positive EVs and expression of cellular EpCAM. These results may contribute to prediction of platinum resistance in the future, although they should first be validated in clinical samples.

Ovarian cancer is the most lethal gynecological malignancy. Poor overall survival, particularly for patients with high grade serous (HGS) ovarian cancer, are often attributed to late stage at diagnosis and relapse following chemotherapy. HGS ovarian cancer is a heterogenous disease in that few genes are consistently mutated between patients. Additionally, HGS ovarian cancer is characterized by high genomic instability. For these reasons personalized approaches may be necessary for effective treatment and cure. Understanding the molecular mechanisms that contribute to tumor metastasis and chemoresistance are essential to improve survival rates. One favored model for tumor metastasis and chemoresistance is the cancer stem cell (CSC) model. CSCs are cells with enhanced self-renewal properties that are enriched following chemotherapy. Elimination of this cell population is thought to be a mechanism to increase therapeutic response. Therefore, accurate identification of stem cell populations that are most clinically relevant is necessary. While many CSC identifiers (ALDH, OCT4, CD133, and side population) have been established, it is still not clear which population(s) will be most beneficial to targeted in patients. Therefore, there is a critical need to characterize CSCs with reliable markers and find their weaknesses that will make the CSCs amenable to therapy. Many signaling pathways are implicated for their roles in CSC initiation and maintenance. Therapeutically targeting pathways needed for CSC initiation or maintenance may be an effective way of treating HGS ovarian cancer patients. In conclusion, the prognosis for HGS ovarian cancer may be improved by combining CSC phenotyping with targeted therapies for pathways involved in CSC maintenance.

Cancer cells utilize a number of mechanisms to increase their survival and progression as well as their resistance to anticancer therapy: deregulation of growth regulatory pathways by acquiring grow factor independence, immune system suppression, reducing the expression of antigens activating T lymphocyte cells (mimicry), induction of anti-apoptotic signals to counter the action of drugs, activation of several DNA repair mechanisms and driving the active efflux of drugs from the cell cytoplasm and epigenetic regulation by microRNAs (miRNAs). Due to the fact that it is commonly diagnosed late, lung cancer remains a major malignancy with a low five-year survival rate; when diagnosed, the cancer is often highly advanced and the cancer cells may have acquired drug resistance. This review summarizes the main mechanisms involved in cisplatin resistance and in interactions between cisplatin-resistant cancer cells and the tumor microenvironment. It also analyses changes in the gene expression profile of cisplatin sensitive vs. cisplatin resistant non–small cell lung cancer (NSCLC) cellular model using the GSE108214 Gene Expression Omnibus database. It describes a protein-protein interaction network that indicates highly-dysregulated TP53, MDM2 and CDKN1A genes as they encodes the top networking proteins that may be involved in cisplatin tolerance, these all being upregulated in cisplatin-resistant cells. Furthermore, it illustrates the multifactorial nature of cisplatin resistance by examining the diversity of dysregulated pathways present in cisplatin-resistant NSCLC cells based on KEGG pathway analysis.

This study analyzes oral supplement of molecular iodine (I2) alone and in combination with the neoadjuvant therapy 5-fluorouracil/epirubicin/cyclophosphamide or taxotere/epirubicin (FEC/TE) in women with Early (stage II) and Advanced (stage III) breast cancer. In the Early group, 30 women were treated with I2 (5 mg/day) or placebo (colored water) for 7–35 days before surgery. For the Advanced group, 30 patients received I2 or placebo along with FEC/TE treatment. After surgery, all patients received FEC/TE + I2 for 170 days. I2 supplementation showed a significant attenuation of the side effects and absence of tumor chemoresistance. Control, I2, FEC/TE, and FEC/TE+I2 groups exhibit response rate of 0, 33%, 73%, and 100%, respectively, and a pathologic complete response of 18%, and 36% in the last two groups. Five-year disease-free survival rate was significantly higher in patients with I2 supplement before and after surgery compared to those receiving the supplement only after surgery (82% vs. 46%). I2-treated tumors exhibit less invasive potential, and significant increases in apoptosis, estrogen receptor expression, and immune cell infiltration. Transcriptomic analysis indicated activation of the antitumoral immune response. The results led us to register a phase III clinical trial analyzing chemotherapy + I2 treatment for advanced breast cancer.

Chronic myeloid leukemia (CML) is the most common form of leukemia in adults and accounts for approximately 15% of all leukemia cases. The etiology of this disease is based on the presence of the oncogenic Bcr/Abl fusion protein, which has dysregulated tyrosine kinase activity. This pathological condition is the result of a chromosomal translocation between chromosomes 9 and 22 leading to the formation of the Philadelphia chromosome (Ph). Clinical establishment of targeted therapy with Abl kinase inhibitors (AKIs) has been observed in the treatment of CML. Therapy resistance in patients with CML is due to genetic alterations in the cells of CML, specifically affecting the Bcr/Abl oncoprotein. Acquired resistance of CML patients to tyrosine kinase inhibitors (AKIs) has also been associated with the tumor microenvironment (TME). This study aimed to examine the role of hypoxic conditions in the development of chemoresistance to certain AKIs in CML. The findings of our study indicate that exposure to hypoxic conditions leads to a substantial increase in chemoresistance to crizotinib, while only resulting in a slight increase in chemoresistance to imatinib. It is worth noting that both drugs effectively block Bcr/Abl function. Furthermore, it was observed that the inclusion of the JAK1/2 inhibitor ruxolitinib resulted in an augmentation of chemoresistance to crizotinib in the context of hypoxia. Overexpression of hypoxia-inducible factor 1a (HIF1a) and silencing of JAK2 confirmed that the two proteins cooperate in mediating chemoresistance to crizotinib in CML cell lines. It is noteworthy that the compound 2-methoxy estradiol (2ME2), which is a metabolite of estradiol lacking estrogenic activity, has shown efficacy in reinstating the sensitivity of CML cells to crizotinib in the presence of hypoxic circumstances. Additionally, when used in conjunction with a JAK2 inhibitor, 2ME2 exhibited activity in restoring crizotinib sensitivity in CML cells. The findings of our study underscore the significance of selectively targeting elements of the HIF1α pathway in order to achieve total eradication of chronic myeloid leukemia (CML) cells.

Chronic myeloid leukemia (CML) is the most common form of leukemia in adults and accounts for approximately 15% of all leukemia cases. The etiology of this disease is based on the presence of the oncogenic Bcr/Abl fusion protein, which has dysregulated tyrosine kinase activity. This pathological condition is the result of a chromosomal translocation between chromosomes 9 and 22 leading to the formation of the Philadelphia chromosome (Ph). Clinical establishment of targeted therapy with Abl kinase inhibitors (AKIs) has been observed in the treatment of CML. Therapy resistance in patients with CML is due to genetic alterations in the cells of CML, specifically affecting the Bcr/Abl oncoprotein. Acquired resistance of CML patients to tyrosine kinase inhibitors (AKIs) has also been associated with the tumor microenvironment (TME). This study aimed to examine the role of hypoxic conditions in the development of chemoresistance to certain AKIs in CML. The findings of our study indicate that exposure to hypoxic conditions leads to a substantial increase in chemoresistance to crizotinib, while only resulting in a slight increase in chemoresistance to imatinib. It is worth noting that both drugs effectively block Bcr/Abl function. Furthermore, it was observed that the inclusion of the JAK1/2 inhibitor ruxolitinib resulted in an augmentation of chemoresistance to crizotinib in the context of hypoxia. Overexpression of hypoxia-inducible factor 1 (HIF1) and silencing of JAK2 confirmed that the two proteins cooperate in mediating chemoresistance to crizotinib in CML cell lines. It is noteworthy that the compound 2-methoxy estradiol (2ME2), which is a metabolite of estradiol lacking estrogenic activity, has shown efficacy in reinstating the sensitivity of CML cells to crizotinib in the presence of hypoxic circumstances. Additionally, when used in conjunction with a JAK2 inhibitor, 2ME2 exhibited activity in restoring crizotinib sensitivity in CML cells. The findings of our study underscore the significance of selectively targeting elements of the HIF1α pathway in order to achieve total eradication of chronic myeloid leukemia (CML) cells.

Due to its built-up chemoresistance after prolonged usage, the demand for replacing platinum in metal-based drugs (MBD) is rising. The first MBD approved by the FDA for cancer therapy was cisplatin in 1978. Even after nearly four and a half decades of trials, there has been no significant improvement in osteosarcoma (OS) therapy. In fact, many MBD have been developed, but the chemoresistance problem raised by platinum remains unresolved. This motivates us to elucidate the possibilities of the copper and zinc (CuZn) combination to replace platinum in MBD. Thus, the anti-chemoresistance properties of CuZn and their physiological functions for OS therapy are highlighted. Herein, we summarise their chelators, main organic solvents, and ligand functions in their structures that are involved in anti-chemoresistance properties. Through this review, it is rational to discuss their ligands’ roles as biosensors in drug delivery systems. Hereafter, an in-depth understanding of their redox and photoactive function relationships is provided. The disadvantage is that the other functions of biosensors cannot be elaborated on here. As a result, this review is being developed, which is expected to intensify OS drugs with higher cure rates. Nonetheless, this advancement intends to solve the major chemoresistance obstacle towards clinical efficacy.

Colony-stimulating factor 1 receptor (CFS-1R) is a myeloid receptor with a crucial role in monocyte survival and differentiation. Its overexpression is associated with aggressive tumor characterized by an immunosuppressive microenvironment and poor prognosis. CSF-1R ligands, IL-34 and M-CSF, are produced by many cells in the tumor microenvironment (TME), suggesting a key role for the receptor in the crosstalk between tumor, immune and stromal cells in the TME. Recently, CSF-1R expression was reported at the cell membrane of cancer cell from different solid tumors, capturing the interest of various research group interested in investigating the role of this receptor in non-myeloid cells. This review summarizes current data available on the expression and activity of CSF-1R in different tumor types. Notably, CSF-1R+ cancer cells have been shown to produce CSF-1R ligands, indicating that CSF-1R signaling is positively regulated in autocrine manner in cancer cells. Recent research demonstrated that CSF-1R signaling enhances cell transformation by supporting tumor cell proliferation, invasion, stemness and drug resistance. In addition, this review covers recent therapeutic strategies, including monoclonal antibodies and small molecule inhibitors, targeting the CSF-1R and designed to block the pro-oncogenic role of CSF-1R in cancer cell.

Never in mitosis gene A-related kinase 2 (NEK2) a member of serine-threonine kinase protein mainly involved in the cell cycle process. Clinical studies revealed NEK2 overexpression in various tumour types, also NEK2 was reported for their association with genetic abnormalities like mitotic machinery deregulation and chromosomal instability. Besides NEK2 plays a key role in maintaining the transformed phenotype of cancer cells and chemo-resistance of several tumour types. Thus, NEK2 transcriptional profile is important for diagnosis, treatment, and prognosis stages of cancer studies. Screening of novel NEK2 inhibitor would be beneficial in developing the specific lead molecules. Our studies involved NEK2 transcriptional profile search, screening of druggable cavities in NEK2, Drug likeliness of mangrove derived naphthoquinone derivatives avicennoneA , avicennoneB , avicennoneC , avicennoneD , avicenoneE , avicennone F , and avicennone G , avicequinone A, stenocarpoquinone B , avicequinone C , avicenol A , avicenol C,brugine, apigenin, chrysin and molecular docking studies to assess MNC compounds binding efficacy towards NEK2. Mangrove derived compounds conferred the intermolecular hydrogen bond, Pi-alkyl,pi-cation interactions with NEK2 kinase domain region residues Tyr 19, Lys 37, Arg 164, Lys174. Nearly 200 kinase proteins contained this promising Cys 22 residue as its positioned in the catalytic site like NEK family proteins. Avicenna A, Avicennone G, Chrysin and Brugine formed the irreversible covalent binding with NEK2 through Cys 22, thus they can be considered as potential kinase inhibitors with the limited off-target response. But these MNC compounds need to be tested further in invitro and invivo studies to propose as potent NEK2 inhibitors.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with complex carcinogenesis. Although there has been significant progress in the treatment of HCC over the past decades, drug resistance to chemotherapy remains a major obstacle in its successful management. In this study we were able to reduce chemoresistance in cisplatin-resistant HepG2 cells by either silencing the expression of transglutaminase type 2 (TG2) using siRNA or by pre-treatment of cells with the TG2 enzyme inhibitor cystamine. Further analysis revealed that, whereas the full-length TG2 isoform (TG2-L) was almost completely cytoplasmic in its distribution, the majority of the short TG2 isoform (TG2-S) was membrane-associated in both parental and chemoresistant HepG2 cells. Following induction of cisplatin toxicity in non-chemoresistant parental cells, TG2-S together with cisplatin quickly relocated to the cytosolic fraction. Conversely, no cytosolic relocalisation of TG2-S or nuclear accumulation cisplatin was observed following identical treatment of chemoresistant cells, where TG2-S remained predominantly membrane-associated. This suggests that deficient subcellular relocalisation of TG2-S from membranous structures into the cytoplasm may limit the apoptic response to cisplatin toxicity in chemoresistant cells. Structural analysis of TG2 revealed the presence of binding motifs for interaction of TG-S with the membrane scaffold protein LC3/LC3 homologue that could contribute to a novel mechanism of chemotherapeutic resistance in HepG2 cells.

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells (CRC-SCs) which stealthily exploit niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored. Experimental approach: In this present study, we employed relatively new bioinformatics approaches, analyses of microarray data, western blot, RT-PCR, and functional assays to show that hsa-miR-324-5p expression is significantly suppressed in CRC cells, and inversely correlates with the aberrant expression of SOD2. Results: This converse hsa-miR-324-5p/SOD2 relationship is associated with enhanced oncogenicity, which is effectively inhibited by 4-AAQB as evidenced by inhibited cell viability and proliferation, as well as, attenuated migration, invasion and clonogenicity in 4-AAQB-treated DLD1 and HCT116 cells. We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins. Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo. Additionally, 4-AAQB synergistically potentiates FOLFOX anticancer effect by eliciting the re-expression of SOD2-suppressed hsa-miR-324 and inhibiting SOD2-mediated tumorigenicity. Conclusion: Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients.

The emergence of chemoresistance in neoplastic cells is one of the major obstacles in cancer therapy. Autophagy was recently reported as one of the mechanisms that promote chemoresistance in cancer cells by protecting from apoptosis and driving senescence. Thus, understanding the role of autophagy and its underlying signaling pathways is crucial for the development of new therapeutic strategies to overcome chemoresistance. We have previously reported that PKCη is a stress-induced kinase that confers resistance in breast cancer cells against chemotherapy by inducing senescence. Here we show that PKCη promotes autophagy induced by ER and oxidative stress and facilitates the transition from autophagy to senescence. We demonstrate that PKCη knockdown reduces both the autophagic flux and markers of senescence. Additionally, using autophagy inhibitors, such as chloroquine and 3-methyladenine, we show that PKCη and autophagy are required for establishing senescence in MCF-7 in response to oxidative stress. Different drugs used in the clinic are known to induce autophagy and senescence in breast cancer cells. Our study proposes PKCη as a target for therapeutic intervention, acting in synergy with autophagy-inducing drugs, to overcome resistance and enhance cell death in breast cancer.

Cancer stem cells play a crucial role in tumor initiation, metastasis and therapy resistance. Cellular heterogeneity and plasticity challenge the isolation of cancer stem cells. The impact of intratumoral cellular heterogeneity in the context of treatment resistance using a label-free approach remains understudied. Here, we use the sedimentation field-flow fractionation technique to separate, without labeling, cell subpopulations of colorectal cancer cell lines and primary cultures according to their biophysical properties. One of the three cell subpopulations sorted by SdFFF exhibits cancer stem cell traits, including high tumorigenicity in vivo, and a higher frequency of tumor-initiating cells compared to the other subpopulations. In vitro two- and three-dimensional chemosensitivity assays emphasize the therapeutic relevance of this cancer stem cell-like subpopulation due to its chemoresistance. Therefore, our findings highlight a label-free cell sorting approach to reveal intratumoral cellular heterogeneity and its implication in therapy resistance. This approach enables the study of the individualized response of each sorted cell subpopulation by breaking down the tumor, thus offering new perspectives for personalized therapy.

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance, culminating in relapse and metastatic disease continue to be associated with fatal disease. Cancer stem cells (CSCs) are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterised in many cancers with data illustrating that CSCs display great abilities to self-renew, withstand therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ABC membrane transporters, activation of several survival signaling pathways and increased immune evasion DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we re-visit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

Background. Malignant pleural mesothelioma (MPM) is still a rather incurable disease. Many classes of compounds with various mechanisms of action have been tested in vivo and ex-vivo, with rather disappointing results. This is partly due to preclinical studies mostly performed in models that fail to recapitulate MPM complexity and do not retain the intra-tumor heterogeneity, a propelling force for tumor progression. Additionally, we and others have shown that, under stress-induced chemotherapy, profound rearrangements take place in MPM cultures to fuel the emergence of chemoresistant cell subpopulations. Thus, finding clinically actionable modulators of MPM resistance is still a very urgent need. Methods. Setup and propagation of patient-derived organoid cultures from MPM pleural effusions; flow cytometry-based validation of organoid cultures, isola-tion and propagation of mesothelioma-associated fibroblasts; co-cultures, Lu-minex-based Cytokine array, ELISA assay to quantitate IL-6 in the conditioned media, qRT-PCR to assess mRNA expression of cancer stem cell markers and fibroblast markers. Results. Organoid cultures were obtained from eight MPM patients by using specific growth media and conditions to propagate pleural effusion-derived cells. We proved that primary MPM specimens and serially passaged (mesothelio-ma-Patient-Derived-Organoids) mPDOs were cytologically similar, with the obtained mPDOs expressing mesothelial markers similarly to the originating specimen. As expected from a clinically relevant model, the size and number of mPDOs were altered, in a patient-specific way, when pharmacologically relevant doses of chemotherapy drugs were added. We derived Mesothelio-ma-Associated-Fibroblasts (MAFs) and the addition of MAFs, to various ratios, altered the response of the mPDOs to pemetrexed + cisplatin, toward a reduced sensitivity to the latter anticancer agents. Additionally, organoid formation and size were altered by MAF-conditioned media, and this correlated with increased expression of cancer stem cell markers. We showed increased levels of IL-6 in the media of the treated cocultures and showed that this latter was derived from the MAFs. Conclusions. Increased secretion of IL-6 by mesothelioma-associated fibroblasts (MAFs) contributes to the resistance of the MPM to therapy.

The vacuolar proton translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism is mainly based on anaerobic glycolytic reactions. Moreover, the neoplastic cells use the V-ATPase to extrude chemotherapy drugs to the extra-cellular compartment, as a drug-resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1 induced-inhibition of V-ATPase in patients-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome the resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 lead to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models that are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem component, encouraging the search for novel strategies to limit its activity in order to get around the resistance to the conventional therapy.

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Besides, from pharmacogenomic research it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1 and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarkers microRNA could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

BACKGROUND: Treatment failure in primary as well as metastatic cancer patients, caused by chemo and radio resistance, has truncated the research for the applicability of personalized medicine. The use of stem cells and cancer stem cells in such a treatment approach will be reviewed in this study. RESULTS: CRC stem cells prove to be a promising asset for CRC treatment optimization both by serving as biomarkers for the current therapy modalities by means of treatment personalization and patient/tumor stratification, as well as in the development of targeted therapies, selective for the stem cell population. Similar conclusions are drawn, regarding mesenchymal stromal cells and their effect in CRC therapy; while resident stromal cells of tumor microenvironment seem to promote the tumorigenic and metastatic processes in addition to conferring to the chemo- and radio resistance, under certain conditions they are able to improve the treatment outcome of CRC chemotherapy, e.g. by targeted enzyme/prodrug treatment of CRC cells. CONCLUSION: This review, truncates the dynamic potential of cancer stem cells and other stem cell types in CRC treatment personalization as well as, in the improvement of current treatment approaches opting to a higher therapeutic rate, improved prognosis, survival and quality of life for CRC patients.

Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER-stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.