miR-34a Regulates Multidrug Resistance via Positively Modulating OAZ2 Signaling in Colon Cancer Cells

Although aberrant expression of miR-34a, an essential tumor suppressor miRNA, has been frequently observed in colon cancer (CCa), whether miR-34a can regulate CCa progression by modulating other facets of this malignancy (such as multidrug resistance, MDR) remains unknown. Here, we report for the first time that miR-34a expression was significantly downregulated in clinical CCa samples from oxaliplatin-resistant patients and in experimentally established multidrug-resistant CCa cells. By using histoculture drug response assay, we further confirmed that clinical CCa samples with lower miR-34a expression appeared to be more resistant to chemotherapy. Functionally, ectopic expression of exogenous miR-34a resensitized multidrug-resistant HCT-8/OR cells to oxaliplatin treatment, whereas miR-34a inhibition augmented the oxaliplatin resistance in chemosensitive HCT-8 cells. Mechanistically, miR-34a positively regulated the mRNA stability of the ornithine decarboxylase antizyme 2 (OAZ2) by directly targeting its three prime untranslated region (3′UTR). Consequently, suppression of the expression of miR-34a/OAZ2 signaling by chemotherapeutic agents significantly enhanced the activation of MDR-associated ATP-binding cassette (ABC) transporters and antiapoptosis pathways, thus leading to MDR development in CCa cells. Collectively, our combined analysis reveals a critical role of miR-34a/OAZ2 cascade in conferring a proper cellular response to CCa chemotherapy.

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lncRNA TUG1 modulates proliferation, apoptosis, invasion, and angiogenesis via targeting miR-29b in trophoblast cells

Human Genomics ◽

10.1186/s40246-019-0237-z ◽

2019 ◽

Vol 13 (1) ◽

Cited By ~ 11

Author(s):

Qian Li ◽

Jing Zhang ◽

Dong-Mei Su ◽

Li-Na Guan ◽

Wei-Hong Mu ◽

...

Keyword(s):

Cell Proliferation ◽

Critical Role ◽

Ectopic Expression ◽

Neonatal Morbidity ◽

Tube Formation ◽

Cell Counting ◽

Luciferase Reporter ◽

Pcr Analysis ◽

Aberrant Expression ◽

Lncrna Tug1

Abstract Background Pre-eclampsia (PE) is regarded as the leading cause of maternal and neonatal morbidity and mortality. Nevertheless, the potential mechanism for the regulation of trophoblast behaviors and the pathogenesis of PE remain largely elusive. Recently, accumulating evidence emphasized that aberrant expression of long non-coding RNAs (lncRNAs) functions as imperative regulators in human diseases, including PE. Thus, identifying PE-related specific lncRNAs to uncover the underlying molecular mechanism is of much significance. However, the functional roles and underlying mechanisms of lncRNAs in PE progression remain unclear. Method Placenta tissues obtained from patients with PE and healthy pregnant women were performed to measure TUG1 expression by qRT-PCR analysis. Transient transfections were conducted to alter TUG1 expression. Cell Counting Kit-8 (CCK-8) and flow cytometry assays were carried out to assess cell proliferation and apoptosis, respectively. Transwell and tube formation assays were performed to measure the capacity of cell invasion and angiogenesis. Moreover, the luciferase reporter assay was subjected to verify the binding relationship between TUG1 and miR-29b. Western blot analysis was performed to detect the expression of key proteins in the PI3K/AKT and ERK pathway. Results Here, we identified a lncRNA, TUG1, which was notably decreased in placental samples of PE patients. Functional experiments of loss- or gain-of-function assays also verified that ectopic expression of TUG1 promoted cell proliferation, invasion, and angiogenesis, but negatively regulated cell apoptosis, whereas TUG1 inhibition presented the opposite effects. Furthermore, mechanistic researches revealed that TUG1 could act as a molecular sponge for miR-29b, thus regulating MCL1, VEGFA, and MMP2 to modulate PE development. Conclusions Taken together, our findings demonstrated that TUG1 exerts as a critical role in PE progression, which might furnish a novel therapeutic marker for PE treatment.

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Impact of Binding to the Multidrug Resistant Regulator Protein LmrR on the Photo-Physics and -Chemistry of Photosensitizers

10.26434/chemrxiv.12052443 ◽

2020 ◽

Author(s):

Sara H Mejías ◽

Gerard Roelfes ◽

wesley browne

Keyword(s):

Multidrug Resistance ◽

Cellular Response ◽

Photophysical Properties ◽

Protoporphyrin Ix ◽

Multidrug Resistant ◽

Eosin Y ◽

Redox Potentials ◽

Regulator Protein ◽

Resistance Protein ◽

Cellular Components

Light activated photosensitizers generate reactive oxygen species (ROS) that interfere with cellular components and can induce cell death, e.g., in photodynamic therapy (PDT). The effect of cellular components and especially proteins on the photochemistry and photophysics of the sensitizers is a key aspect in drug design and the correlating cellular response with the generation of specific ROS species. Here, we show the complex range of effects of binding of photosensitizer to a multidrug resistance protein, produced by bacteria, on the formers reactivity. We show that recruitment of drug like molecules by LmrR (Lactococcal multidrug resistance Regulator) modifies their photophysical properties and their capacity to induce oxidative stress especially in 1O2 generation, including rose bengal (RB), protoporphyrin IX (PpIX), bodipy, eosin Y (EY), riboflavin (RBF), and rhodamine (Rh6G). The range of neutral and charged dyes with different exited redox potentials, are broadly representative of the dyes used in PDT.

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Amplified Antitumor Efficacy By A Targeted Drugs Retention and Chemosensitization Strategies-Based “Combo” Nanoagent Together With PD-L1 Blockade In Reversing Multidrug Resistance

10.21203/rs.3.rs-492081/v1 ◽

2021 ◽

Author(s):

Weixi Jiang ◽

Lei Su ◽

Meng Ao ◽

Xun Guo ◽

Chen Cheng ◽

...

Keyword(s):

Multidrug Resistance ◽

Photoacoustic Imaging ◽

Critical Role ◽

Metastatic Tumor ◽

Chemotherapeutic Agents ◽

Antitumor Efficacy ◽

Glycoprotein P ◽

Immunological Responses ◽

Low Efficiency ◽

Syngeneic Tumors

Abstract Background: Recent studies have demonstrated that multidrug resistance (MDR) plays a critical role in the low efficiency of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of chemotherapeutic agents. Results: In this study, we fabricated a “combo” nanoagent equipped with triple synergistic strategies for enhancing antitumor efficacy against MDR cells. Tumor homing-penetrating peptide endows the nanosystem with targeting and penetrating capabilities in the first stage of tumor internalization. The abundant amine groups of polyethylenimine (PEI)-modified nanoparticles then trigger a proton sponge effect to promote endo/lysosomal escape that enhances the intracellular accumulation and retention of anticancer drugs. Furthermore, copper tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) encapsulated in the nanosystem, effectively scavenges endogenous glutathione (GSH) to relieve the detoxification mediated by GSH and sensitize the cancer cells to drugs, while simultaneously serving as a photoacoustic imaging (PAI) contrast agent for image visualization. Moreover, we also verify that the versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can not only activate immunological responses but also inhibit P-gp expression to obliterate primary and metastatic tumor. Conclusion: This work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors compared to an equivalent dose of free paclitaxel by using multiple MDR reversing strategies.

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Insulin enhancement of the antitumor activity of chemotherapeutic agents in colorectal cancer is linked with downregulating PIK3CA and GRB2

Scientific Reports ◽

10.1038/s41598-019-53145-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Siddarth Agrawal ◽

Marta Woźniak ◽

Mateusz Łuc ◽

Sebastian Makuch ◽

Ewa Pielka ◽

...

Keyword(s):

Colon Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Western Blotting ◽

Expression Patterns ◽

Critical Role ◽

Chemotherapeutic Agents ◽

Significant Inhibition

Abstract The present state of cancer chemotherapy is unsatisfactory. New anticancer drugs that marginally improve the survival of patients continue to be developed at an unsustainably high cost. The study aimed to elucidate the effects of insulin (INS), an inexpensive drug with a convincing safety profile, on the susceptibility of colon cancer to chemotherapeutic agents: 5-fluorouracil (FU), oxaliplatin (OXA), irinotecan (IRI), cyclophosphamide (CPA) and docetaxel (DOC). To examine the effects of insulin on cell viability and apoptosis, we performed an in vitro analysis on colon cancer cell lines Caco-2 and SW480. To verify the results, we performed in vivo analysis on mice bearing MC38 colon tumors. To assess the underlying mechanism of the therapy, we examined the mRNA expression of pathways related to the signaling downstream of insulin receptors (INSR). Moreover, we performed Western blotting to confirm expression patterns derived from the genetic analysis. For the quantification of circulating tumor cells in the peripheral blood, we used the maintrac method. The results of our study show that insulin-pretreated colon cancer cells are significantly more susceptible to commonly used chemotherapeutics. The apoptosis ratio was also enhanced when INS was administered complementary to the examined drugs. The in vivo study showed that the combination of INS and FU resulted in significant inhibition of tumor growth and reduction of the number of circulating tumor cells. This combination caused a significant downregulation of the key signaling substrates downstream of INSR. The results indicate that the downregulation of PIK3CA (phosphatidylinositol 3-kinase catalytic subunit alpha), which plays a critical role in cell signaling and GRB2 (growth factor receptor-bound protein 2), a regulator of cell proliferation and differentiation may be responsible for the sensitizing effect of INS. These findings were confirmed at protein levels by Western blotting. In conclusion, these results suggest that INS might be potentially applied to clinical use to enhance the therapeutic effectiveness of chemotherapeutic drugs. The findings may become a platform for the future development of new and inexpensive strategies for the clinical chemotherapy of tumors.

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Role of Wnt/β-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer

BioMed Research International ◽

10.1155/2020/9390878 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Shengli Yuan ◽

Fengying Tao ◽

Xinglin Zhang ◽

Yan Zhang ◽

Xingxing Sun ◽

...

Keyword(s):

Colorectal Cancer ◽

Multidrug Resistance ◽

Critical Role ◽

Tumor Development ◽

Chemotherapeutic Agents ◽

High Morbidity ◽

Regulatory Effects ◽

Underlying Mechanisms ◽

Common Malignancy

Colorectal cancer (CRC) is a common malignancy with high morbidity and mortality worldwide. To date, chemotherapy plays an important role in the treatment of CRC patients. Multidrug resistance (MDR) is one of the major hurdles in chemotherapy for CRC, and the underlying mechanisms need to be explored. Studies have demonstrated that Wnt/β-catenin signaling plays a critical role in oncogenesis and tumor development, and its function in inhibiting apoptosis could facilitate tumor chemoresistance. Recent investigations have also suggested the regulatory effects of the Wnt/β-catenin signaling pathway in response to chemotherapeutic agents in CRC. Here, we particularly focus on reviewing the evidences suggesting the mechanisms of Wnt/β-catenin signaling in the chemoresistance modulation of colorectal cancer.

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Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo

Frontiers in Pharmacology ◽

10.3389/fphar.2021.798837 ◽

2022 ◽

Vol 12 ◽

Author(s):

Gangyang Wang ◽

Lingling Cao ◽

Yafei Jiang ◽

Tao Zhang ◽

Hongsheng Wang ◽

...

Keyword(s):

Multidrug Resistance ◽

Mouse Model ◽

Atpase Activity ◽

Multidrug Resistant ◽

Chemotherapeutic Agents ◽

Protein Expression Level ◽

Nude Mouse Model ◽

P Glycoprotein

Overexpression of the multidrug resistance (MDR)-related protein P-glycoprotein (PGP1), which actively extrudes chemotherapeutic agents from cells and significantly decreases the efficacy of chemotherapy, is viewed as a major obstacle in osteosarcoma chemotherapy. Anlotinib, a novel tyrosine kinase inhibitor (TKI), has good anti-tumor effects in a variety of solid tumors. However, there are few studies on the mechanism of anlotinib reversing chemotherapy resistance in osteosarcoma. In this study, cellular assays were performed in vitro and in vivo to evaluate the MDR reversal effects of anlotinib on multidrug-resistant osteosarcoma cell lines. Drug efflux and intracellular drug accumulation were measured by flow cytometry. The vanadate-sensitive ATPase activity of PGP1 was measured in the presence of a range of anlotinib concentrations. The protein expression level of ABCB1 was detected by Western blotting and immunofluorescence analysis. Our results showed that anlotinib significantly increased the sensitivity of KHOSR2 and U2OSR2 cells (which overexpress PGP1) to chemotherapeutic agents in vitro and in a KHOSR2 xenograft nude mouse model in vivo. Mechanistically, anlotinib increases the intracellular accumulation of PGP1 substrates by inhibiting the efflux function of PGP1 in multidrug-resistant cell lines. Furthermore, anlotinib stimulated the ATPase activity of PGP1 but affected neither the protein expression level nor the localization of PGP1. In animal studies, anlotinib in combination with doxorubicin (DOX) significantly decreased the tumor growth rate and the tumor size in the KHOSR2 xenograft nude mouse model. Overall, our findings suggest that anlotinib may be useful for circumventing MDR to other conventional antineoplastic drugs.

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Impact of Binding to the Multidrug Resistant Regulator Protein LmrR on the Photo-Physics and -Chemistry of Photosensitizers

10.26434/chemrxiv.12052443.v1 ◽

2020 ◽

Author(s):

Sara H Mejías ◽

Gerard Roelfes ◽

wesley browne

Keyword(s):

Multidrug Resistance ◽

Cellular Response ◽

Photophysical Properties ◽

Protoporphyrin Ix ◽

Multidrug Resistant ◽

Eosin Y ◽

Redox Potentials ◽

Regulator Protein ◽

Resistance Protein ◽

Cellular Components

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Synthesis and Anticancer Cytotoxicity of Azaaurones Overcoming Multidrug Resistance

Molecules ◽

10.3390/molecules25030764 ◽

2020 ◽

Vol 25 (3) ◽

pp. 764 ◽

Cited By ~ 2

Author(s):

Szilárd Tóth ◽

Áron Szepesi ◽

Viet-Khoa Tran-Nguyen ◽

Balázs Sarkadi ◽

Katalin Német ◽

...

Keyword(s):

Multidrug Resistance ◽

Anticancer Drugs ◽

Multidrug Resistant ◽

Chemotherapeutic Agents ◽

Cancer Resistance ◽

Selective Toxicity ◽

Multidrug Resistance Protein 1 ◽

New Class ◽

Resistance Protein

The resistance of tumors against anticancer drugs is a major impediment for chemotherapy. Tumors often develop multidrug resistance as a result of the cellular efflux of chemotherapeutic agents by ABC transporters such as P-glycoprotein (ABCB1/P-gp), Multidrug Resistance Protein 1 (ABCC1/MRP1), or Breast Cancer Resistance Protein (ABCG2/BCRP). By screening a chemolibrary comprising 140 compounds, we identified a set of naturally occurring aurones inducing higher cytotoxicity against P-gp-overexpressing multidrug-resistant (MDR) cells versus sensitive (parental, non-P-gp-overexpressing) cells. Follow-up studies conducted with the P-gp inhibitor tariquidar indicated that the MDR-selective toxicity of azaaurones is not mediated by P-gp. Azaaurone analogs possessing pronounced effects were then designed and synthesized. The knowledge gained from structure–activity relationships will pave the way for the design of a new class of anticancer drugs selectively targeting multidrug-resistant cancer cells.

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