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Metformin and 2-deoxyglucose(2DG) combination enhanced the cytotoxicity of doxorubicin in MCF-7/ Dox cells. A, B. MCF-7 and MCF-7/Dox cells were treated with metformin(0.3, 0.5, 1 mM) and 2DG(0.3, 0.5, 1 mM) for 24h, and
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Multidrug resistance(MDR) is a major obstacle to efficiency of breast cancer chemotherapy. We investigated whether combination of metformin and 2-deoxyglucose reverses MDR of MCF-7/Dox cells and tried to elucidate the possible mechanisms. The combination of metformin and 2-deoxyglucose selectively enhanced cytotoxicity of doxorubicin against MCF-7/...
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Introduction:
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Objective
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Citations
... Lately, several studies have reported that metformin not only inhibits cell proliferation in breast, gastric, ovarian, and small cell lung cancers [8][9][10][11] but also potentiates the cytotoxic effect of some TKIs in bladder, colorectal, and non-small cell lung cancer [12][13][14]. In addition, it is also known to reverse multidrug resistance by regulating cancer stem cell population or signaling [15][16][17]. However, the effects of metformin on CML have not been elucidated. ...
Background/aims:
Nilotinib is used for treating patients with imatinib-sensitive or -resistant chronic myeloid leukemia (CML); however, nilotinib-resistant cases have been observed in recent years. In addition, a considerable number of patients receiving nilotinib developed diabetes. Metformin is a front-line drug for the treatment of type 2 diabetes, and several studies have shown that diabetes patients treated with metformin have reduced incidence of cancer. This study aimed to define the effect of metformin on CML cells to determine whether metformin overcomes nilotinib resistance, and to identify novel targets for the treatment of nilotinib resistance.
Methods:
We observed the effects of metformin and nilotinib on K562 and KU812 human CML cell lines. Nilotinib-resistant CML cell lines were generated by exposing cells to gradually increasing doses of nilotinib. Then, we investigated the driving force that makes resistance to nilotinib and the effect of metformin on the driving force.
Results:
Sub-toxic doses of metformin enhanced nilotinib efficacy by reducing Bcl-xL expression, which induces apoptosis in CML cells. Next, we generated nilotinib-resistant K562 and KU812 cell lines that overexpressed the c-Jun N-terminal kinase (JNK) gene. JNK silencing by a JNK inhibitor restored sensitivity to nilotinib. Furthermore, metformin was effective in decreasing phosphorylated JNK levels, restoring nilotinib sensitivity. Combined treatment with nilotinib and metformin was more effective than combined treatment with nilotinib and a JNK inhibitor in terms of cell proliferation inhibition.
Conclusions:
This study suggested that combination therapy with metformin and nilotinib may have clinical benefits of enhancing antileukemia efficacy and overcoming resistance to nilotinib.
... These transporters can excrete drugs with different structures and different mechanisms of action, resulting in decreased drug concentration in tumor cells, affecting the toxic effects of chemotherapy drugs on tumor cells. [69][70][71] The expression of sorcin and transporters in tumor-resistant cells is summarized as shown in Tables 1 and 2. ...
Soluble resistance-related calcium-binding protein (sorcin) is a member of the penta-EF-hand protein family. Sorcin is widely distributed in normal human tissues, such as the brain, heart, lymphocytes, kidneys, breast and skin. Findings suggest that sorcin is associated with the regulation of calcium homeostasis, cell cycle and vesicle trafficking. It has been reported that many types of non-neoplastic diseases such as diabetes, viral infection, infertility, and nervous system diseases were affected by the expression of sorcin. One of the main issues is the role of sorcin in neoplastic diseases. Research proved that sorcin can be found to overexpress in cells of several cancers, particularly in the case of multidrug-resistant cancers. Additionally, the researchers proposed that the expression of sorcin was significantly associated with the foundation of multidrug resistance (MDR). All the findings mentioned above emphasized the importance of studying sorcin. This review mainly includes the following aspects: functions of sorcin, role in non-neoplastic and neoplastic diseases, and research related to drugs. To sum up, sorcin is a potential novel target to be studied to deal with MDR.
... The therapy reversing Multidrug-resistant (MDR. 81 DOX + 2FDG Increase Phospho-AMPK by combination but decrease phospho-Akt and phospho-ERK expressions. 82 Tamoxifen Combination synergistically inhibits proliferation, DNA replication and trigger apoptosis with reduced dose involving in BAX/BCL-2 apoptotic pathway and AMPK/mTOR/p70S6 growth pathway. ...
Metformin, a well-acknowledged biguanide, safety profile and multiaction drug with low cost for management of type 2 diabetes, makes a first-class candidate for repurposing. The off-patent drug draws huge attention for repositioned for anticancer drug delivery recently. Still few unanswered questions are challenging, among them one leading question; can metformin use as a generic therapy for all breast cancer subtypes? And is metformin able to get over the problem of drug resistance? The review focused on the mechanisms of metformin action specifically for breast cancer therapy and overcoming the resistance; also discusses preclinical and ongoing and completed clinical trials. The existing limitation such as therapeutic dose specifically for cancer treatment, resistance of metformin in breast cancer and organic cation transporters heterogeneity of the drug opens up a new pathway for improved understanding and successful application as repurposed effective chemotherapeutics for breast cancer. However, much more additional research is needed to confirm the accurate efficacy of metformin treatment for prevention of cancer and its recurrence.
... Several previous studies have demonstrated that MET could inhibit the expression of HIF1α, Pgp in tumor cells, animal xenografts, or even patient-derived xenografts. 32,57,58,69 Therefore, HIF1α suppression through AMPK/mTOR activation might be another mechanism to explain the hypoxia improvement of MET, which is beneficial for reversing drug resistance and increasing DOX sensitivity. ...
Doxorubicin (DOX) is a first-line chemo drug for cancer therapy, yet it fails to treat multidrug resistant tumors. Hypoxia is a major reason causing failure in chemotherapy. Particularly, hypoxia up-regulates its responsive transcription factor - hypoxia-inducible factors (HIF) to induce the overexpression of drug resistant genes. Metformin (MET) is recently found to cooperate with DOX against multiple tumors. As a mitochondrial inhibitor, MET could suppress tumor oxygen consumption, and thereby modulate hypoxic tumor microenvironment. In this study, we used cationic liposomes to co-deliver both DOX and MET for treating multidrug resistant breast cancer cells - MCF7/ADR. Faster release of MET enhanced cytotoxicity of DOX through attenuating hypoxic stress both in vivo and in vitro. MET reduced the cellular oxygen consumption and inhibit HIF1α and P-glycoprotein (Pgp) expression in vitro. In addition, the dual drug loaded liposomes increased tumor targeting and intratumoral blood oxygen saturation, which suggested that the tumor reoxygenation effect of MET facilitated to exert its synergistic activity with DOX against MCF7/ADR xenografts. In general, our study represents a feasible strategy to boost therapeutic effect in treating multidrug resistant cancer by improving the hypoxic tumor microenvironment.
... Increasing studies have revealed that P53 inhibits tumor cell proliferation in association with apoptosis signaling, and MDR1, an adenosine triphosphate combined transporter (ABC), triggers drug efflux. Both these proteins showed the most relevance to tumor MDR [26,27]. The results of the present study relying on the increasing expression of P53 and the decrease of MDR1 supported the mechanism for regulation of hsa-miRNA-143-3p to MDR, laying the foundation to the further examine the hsa-miRNA-143-3p/CIAPIN1 pathway. ...
Purpose
Multidrug resistance (MDR) remains a major obstacle in the treatment of triple-negative breast cancer (TNBC) with conventional chemotherapeutic agents. A previous study demonstrated that hsa-miRNA-143-3p plays a vital role in drug resistance of TNBC. Downregulation of hsa-miRNA-143-3p upregulated the expression of its target protein cytokine-induced apoptosis inhibitor 1 (CIAPIN1) in order to activate MDR, while upregulation of hsa-miRNA-143-3p effectively enhances the sensitivity of drug-resistant TNBC cells to chemotherapeutics. The present study aimed to further verify these findings in vivo.
Methods
We established a hypodermic tumor nude mice model using paclitaxel-resistant TNBC cells. We expressed ectopic hsa-miRNA-143-3p under the control of a breast cancer-specific human mammaglobin promoter that guided the efficient expression of exogenous hsa-miRNA-143-3p only in breast cancer cells. Thereafter, we overexpressed hsa-miRNA-143-3p in xenografts using a recombinant virus system and quantified the expression of hsa-miRNA-143-3p, CIAPIN1 protein, and proteins encoded by related functional genes by western blot.
Results
We successfully completed the prospective exploration of the intravenous virus injection pattern from extensive expression to targeted expression. The overexpression of hsa-miRNA-143-3p significantly alleviated chemoresistance of TNBC by inhibiting viability. In addition, we observed that the expression of CIAPIN1 as a hsa-miRNA-143-3p target protein was remarkably decreased.
Conclusion
We partly illustrated the mechanism underlying the hsa-miRNA-143-3p/CIAPIN1 drug resistance pathway. HsamiRNA-143-3p as a tumor suppressive microRNA may be a novel target to effectively reverse MDR of TNBC in vivo.
... K562/ADR cells were seeded into six-well plates in the density of 1 × 10 6 /well and treated with indicated drugs for 48 hr. After pretreating, cells were stained with corresponding dyes according to the manufacturer's instructions and examined by flow cytometric analysis (FACScalibur, BD;Sun et al., 2018;Xue et al., 2017). ...
Though the advancement of chemotherapy drugs alleviates the progress of cancer, long‐term therapy with anticancer agents gradually leads to acquired multidrug resistance (MDR), which limits the survival outcomes in patients. It was shown that dihydromyricetin (DMY) could partly reverse MDR by suppressing P‐glycoprotein (P‐gp) and soluble resistance‐related calcium‐binding protein (SORCIN) independently. To reverse MDR more effectively, a new strategy was raised, that is, circumventing MDR by the coadministration of DMY and ondansetron (OND), a common antiemetic drug, during cancer chemotherapy. Meanwhile, the interior relation between P‐gp and SORCIN was also revealed. The combination of DMY and OND strongly enhanced antiproliferative efficiency of adriamycin (ADR) because of the increasing accumulation of ADR in K562/ADR‐resistant cell line. DMY could downregulate the expression of SORCIN and P‐gp via the ERK/Akt pathways, whereas OND could not. In addition, it was proved that SORCIN suppressed ERK and Akt to inhibit P‐gp by the silence of SORCIN, however, not vice versa. Finally, the combination of DMY, OND, and ADR led to G2/M cell cycle arrest and apoptosis via resuming P53 function and restraining relevant proteins expression. These fundamental findings provided a promising approach for further treatment of MDR. Soluble resistance‐related calcium‐binding protein suppressed expression of P‐glycoprotein via ERK/Akt signaling pathways. Coadministration of dihydromyricetin and ondansetron could strongly enhance the antiproliferative efficiency of adriamycin (ADR) by promoting ADR‐induced G2/M cell cycle arrest and apoptosis.
... Thus, this observation led us to conclude that metformin interferes with GLUT. Interestingly enough, these results are in agreement with the results of Xue et al., showing that metformin strongly increased glucose uptake and lactate production and that 2-DG suppressed glycolysis and prevented metformin-induced glucose uptake and lactate production in MCF-7 and MCF-7/Dox cells [30]. In the MDA-MB-231 cell line, combined treatment of metformin with 2-DG was described to induce detachment of the cells and to suppress cell proliferation [31]. ...
This work aimed to investigate the effect of metformin on cellular glucose uptake and metabolism by breast cancer cells, as a mechanism contributing to its anticancer properties. Estrogen and progesterone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell lines were used as in vitro models of breast cancer. Short-term (26 min) exposure of MCF-7 and MDA-MB-231 cells to metformin inhibited uptake of 3 H-deoxy-D-glucose (3 H-DG). In contrast, long-term (24 h) exposure to metformin (5 μM-1 mM) concentration-dependently increased 3 H-DG uptake in both cell lines. This effect was associated with an increase in lactate production but was not associated with changes in GLUT1 mRNA expression. Long-term exposure of MCF-7 and MDA-MB-231 cells to metformin (5 μM-1 mM) concentration-dependently reduced cell viability and culture mass and slightly increased cell proliferation rates. Combination of metformin (1 mM) with the facilitative glucose transporter (GLUT) inhibitor kaempferol (30 μM) did not change the effect of metformin on culture growth. In conclusion, short-term exposure to metformin reduces cellular glucose uptake, probably by direct inhibition of GLUT1. However, after long-term exposure to metformin, cellular uptake of glucose is significantly increased, not associated to changes in GLUT1 transcription rates. We suggest that, in the long-term, metformin induces a compensatory increase in glucose uptake in response to cellular energy depletion resulting from its inhibitory effect on mitochondrial oxidative phosphorylation machinery. Metformin-induced dependence of breast cancer cells on glycolytic pathway, associated with an anticarcinogenic effect of the drug, provides a biochemical basis for the design of new therapeutic strategies.
... Recent studies have shown that metformin exerts multiple antitumor effects in vivo and in vitro. (24)(25)(26) However, these antitumor effects as well as the related underlying mechanisms vary among different cancer cells. In colorectal cancer, metformin suppresses colonic epithelial proliferation by inhibiting the mTOR pathway via AMPK activation. ...
Metformin is the most commonly used drug for type 2 diabetes and has potential benefit in treating and preventing cancer. Previous studies indicated that membrane proteins can affect the antineoplastic effects of metformin and may be crucial in the field of cancer research. However, the antineoplastic effects of metformin and its mechanism in gallbladder cancer (GBC) remain largely unknown. In this study, the effects of metformin on GBC cell proliferation and viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay and an apoptosis assay. Western blotting was performed to investigate related signaling pathways. Of note, inhibition, knockdown and up-regulation of the membrane protein Chloride intracellular channel 1 (CLIC1) can affect GBC resistance in the presence of metformin. Our data demonstrated that metformin apparently inhibits the proliferation and viability of GBC cells. Metformin promoted cell apoptosis and increased the number of early apoptotic cells. We found that metformin can exert growth-suppressive effects on these cell lines via inhibition of p-Akt activity and the Bcl-2 family. Notably, either dysfunction or down-regulation of CLIC1 can partially decrease the antineoplastic effects of metformin while up-regulation of CLIC1 can increase drug sensitivity. Our findings provide experimental evidence for using metformin as an antitumor treatment for gallbladder carcinoma. This article is protected by copyright. All rights reserved.
Doxorubicin (DOX) is a highly effective chemotherapeutic drug, but its long-term use can cause cardiotoxicity and drug resistance. Accumulating evidence demonstrates that p53 is directly involved in DOX toxicity and resistance. One of the primary causes for DOX resistance is the mutation or inactivation of p53. Moreover, because the non-specific activation of p53 caused by DOX can kill non-cancerous cells, p53 is a popular target for reducing toxicity. However, the reduction in DOX-induced cardiotoxicity (DIC) via p53 suppression is often at odds with the antitumor advantages of p53 reactivation. Therefore, in order to increase the effectiveness of DOX, there is an urgent need to explore p53-targeted anticancer strategies owing to the complex regulatory network and polymorphisms of the p53 gene. In this review, we summarize the role and potential mechanisms of p53 in DIC and resistance. Furthermore, we focus on the advances and challenges in applying dietary nutrients, natural products, and other pharmacological strategies to overcome DOX-induced chemoresistance and cardiotoxicity. Lastly, we present potential therapeutic strategies to address key issues in order to provide new ideas for increasing the clinical use of DOX and improving its anticancer benefits.
Simple Summary
An analysis of metformin (MET) treatment in combination with temozolomide (TMZ) in two glioblastoma cell lines, U87MG and A172, stimulated with lipopolysaccharide (LPS), a TLR4 agonist was conducted. Both cells presented blunted mitochondrial respiration leading to oxidative stress after MET treatment, and decreased cell viability after MET + TMZ treatment. U87MG cells presented increased apoptosis after MET + LPS + TMZ treatment by increment of ER stress, and downregulation of BLC2. A172, with an upregulated antioxidant background, including SOD1, exhibited cell cycle arrest after MET + TMZ treatment. The observed differential response was associated with a distinct metabolic status: glycolytic/plurimetabolic (GPM) subtype in U87MG and mitochondrial (MTC) in A172. TCGA-GBM-RNASeq in silico analysis showed that GPM-GBM cases with an activated TLR4 pathway might respond to MET, but the concomitant CXCL8/IL8 upregulation may demand a combination treatment with an IL8 inhibitor. MET combined with an antioxidant inhibitor, such as anti-SOD1, may be indicated for MTC-GBM cases.
Abstract
Glioblastoma (GBM) is an aggressive brain cancer associated with poor overall survival. The metabolic status and tumor microenvironment of GBM cells have been targeted to improve therapeutic strategies. TLR4 is an important innate immune receptor capable of recognizing pathogens and danger-associated molecules. We have previously demonstrated the presence of TLR4 in GBM tumors and the decreased viability of the GBM tumor cell line after lipopolysaccharide (LPS) (TLR4 agonist) stimulation. In the present study, metformin (MET) treatment, used in combination with temozolomide (TMZ) in two GBM cell lines (U87MG and A172) and stimulated with LPS was analyzed. MET is a drug widely used for the treatment of diabetes and has been repurposed for cancer treatment owing to its anti-proliferative and anti-inflammatory actions. The aim of the study was to investigate MET and LPS treatment in two GBM cell lines with different metabolic statuses. MET treatment led to mitochondrial respiration blunting and oxidative stress with superoxide production in both cell lines, more markedly in U87MG cells. Decreased cell viability after MET + TMZ and MET + LPS + TMZ treatment was observed in both cell lines. U87MG cells exhibited apoptosis after MET + LPS + TMZ treatment, promoting increased ER stress, unfolded protein response, and BLC2 downregulation. LPS stimulation of U87MG cells led to upregulation of SOD2 and genes related to the TLR4 signaling pathway, including IL1B and CXCL8. A172 cells attained upregulated antioxidant gene expression, particularly SOD1, TXN and PRDX1-5, while MET treatment led to cell-cycle arrest. In silico analysis of the TCGA-GBM-RNASeq dataset indicated that the glycolytic plurimetabolic (GPM)-GBM subtype had a transcriptomic profile which overlapped with U87MG cells, suggesting GBM cases exhibiting this metabolic background with an activated inflammatory TLR4 pathway may respond to MET treatment. For cases with upregulated CXCL8, coding for IL8 (a pro-angiogenic factor), combination treatment with an IL8 inhibitor may improve tumor growth control. The A172 cell line corresponded to the mitochondrial (MTC)-GBM subtype, where MET plus an antioxidant inhibitor, such as anti-SOD1, may be indicated as a combinatory therapy.
