Metformin and blood cancers

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Term Occurence Count Dictionary
hyperglycemia 1 endocrinologydiseases
metformin 76 endocrinologydiseasesdrugs
obesity 10 endocrinologydiseases
prednisone 2 endocrinologydiseasesdrugs
type 2 diabetes mellitus 2 endocrinologydiseases
Insulin 1 endocrinologydiseasesdrugs
cyclophosphamide 2 endocrinologydiseasesdrugs
dexamethasone 4 endocrinologydiseasesdrugs
bortezomib 3 endocrinologydiseasesdrugs
diabetes mellitus 5 endocrinologydiseases
hyperinsulinemia 2 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Insulin 16912 chemosensitivity of ALL through its inhibitory effects on the AKT/mTOR pathway via AMPK activation [155],[156]. Insulin might contribute to the chemoresistance of ALL cells by activating PI3K/AKT/mTOR signaling. IGF-1 signaling
bortezomib 15229 mTOR [148].Notably, metformin inhibits glucose regulatory protein 78 (GRP78), an essential factor in bortezomib -induced autophagy and pharmacologically increases the anti-myeloma effects of bortezomib. Concomitant
bortezomib 15318 factor in bortezomib-induced autophagy and pharmacologically increases the anti-myeloma effects of bortezomib . Concomitant treatment with metformin and bortezomib inhibits the effects of the unfolded protein response
bortezomib 15371 pharmacologically increases the anti-myeloma effects of bortezomib. Concomitant treatment with metformin and bortezomib inhibits the effects of the unfolded protein response (UPR) on GRO78, thus impairing autophagosome formation
cyclophosphamide 30641 CLL: chronic lymphocytic leukemia, DA-EPOCHR: dose-adjusted etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin + rituximab, MM: multiple myeloma, NHL: non-Hodgkin lymphoma, DLBCL: diffuse large B cell
cyclophosphamide 30792 multiple myeloma, NHL: non-Hodgkin lymphoma, DLBCL: diffuse large B cell lymphoma, R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone, USA: United States of America
dexamethasone 14881 in the advanced stages [105]. In accordance, in vitro and in vivo, the combination of metformin and dexamethasone synergizes to eliminate MM cells, inhibiting cell proliferation through reduced AKT/mTOR signaling [146].
dexamethasone 17095 PI3K/AKT/mTOR signaling. IGF-1 signaling increases the proliferation of cell lines [157],[158] and inhibits dexamethasone -induced apoptosis [158], promoting the growth of malignant cells. Thus, elevated levels of exogenous
dexamethasone 29591 or CLL*Recurrent/refractoryPilotRitonavirUSA*NCT02948283MM*Recurrent/refractoryPhase IIHigh doses of dexamethasone BR*NCT02967276*MM: multiple myeloma, CLL: chronic lymphocytic leukemia, USA: United States of America,
dexamethasone 30044 diseasePilotNoneUSA*NCT01750567CLL* or MM*Recurrent/refractoryPilotRitonavirUSA*NCT02948283ALLRelapsedPhase IVincristine, dexamethasone , doxorubicin, and PEG-asparaginaseUSA*NCT01324180AML*Relapsed and refractoryPhase ICytarabineUSA*NCT01849276NHL*
metformin 479 classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin , enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation
metformin 617 but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in
metformin 1015 elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article,
metformin 1184 lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.INTRODUCTIONBased
metformin 2235 Notably, the incidence of tumors in patients with DM2 is profoundly affected by the treatment—long-term metformin use has been found to be connected with a reduced incidence of cancer and cancer-related mortality [2].In
metformin 2507 cancers and diabetes and the epidemiological, clinical, and preclinical data that establish the value of metformin as a potential treatment for hematologic malignancies are summarized.Diabetes and cancerAlthough the
metformin 6107 [54],[55].Antihyperglycemic agents and the risk of cancerEarly studies have observed that compared to no therapy, metformin monotherapy is correlated with a reduced risk of developing cancer, whereas sulfonylurea therapy is
metformin 7467 meta-analysis of 182 randomized controlled trials including 135,540 patients with diabetes linked the use of metformin and thiazolidinediones (TZDs) with a reduced risk of cancer [69]. These reviews suggest that the insulin
metformin 7678 insulin level is not a surrogate marker of cancer development, thereby indicating a unique mechanism of metformin activity in cancer.Metformin, cancer, and onco-hematological diseasesHistory of metforminMetformin is
metformin 7768 mechanism of metformin activity in cancer.Metformin, cancer, and onco-hematological diseasesHistory of metformin Metformin is a derivative of biguanide that has been used for nearly one century to treat DM2. Biguanides
metformin 9033 reduced serum glucose levels, including dimethyl biguanide (1,1-dimethyl biguanide hydrochloride or metformin ), were synthesized. Jean Sterne (1909-1997) was the first to perform studies with galegine. Sterne selected
metformin 9171 Sterne (1909-1997) was the first to perform studies with galegine. Sterne selected dimethyl biguanide ( metformin ) for clinical development and proposed the name Glucophage. In contrast to sulfonylureas, metformin
metformin 9271 (metformin) for clinical development and proposed the name Glucophage. In contrast to sulfonylureas, metformin fails to induce insulin secretion but impedes the release of glucose by the liver and increases muscle
metformin 9435 release of glucose by the liver and increases muscle glucose uptake [71].Interestingly, the benefits of metformin in the treatment of diabetes have gained prominence only since 1995. The United Kingdom Prospective
metformin 9637 Prospective Diabetes Study (UKPDS) was a milestone project showing that regardless of glycemic control, metformin reduced the risk of myocardial infarction and all-cause mortality. Consequently, diabetes experts around
metformin 9772 myocardial infarction and all-cause mortality. Consequently, diabetes experts around the world indicated metformin as the first-choice drug for DM2 [70], and metformin has become the most frequently administered agent
metformin 9825 Consequently, diabetes experts around the world indicated metformin as the first-choice drug for DM2 [70], and metformin has become the most frequently administered agent to treat DM2 [72],[73]. In 1995, the benefits of metformin
metformin 9934 has become the most frequently administered agent to treat DM2 [72],[73]. In 1995, the benefits of metformin in people with diabetes were found to not only be limited to glycemic control, and metformin was shown
metformin 10027 benefits of metformin in people with diabetes were found to not only be limited to glycemic control, and metformin was shown to reduce the risk of malignancy in patients with diabetes. Evans et al. [2] were the first
metformin 10195 with diabetes. Evans et al. [2] were the first group to note an inverse correlation between cancer and metformin use, wherein patients who were exposed to metformin had a low risk of developing cancer. Since then,
metformin 10247 note an inverse correlation between cancer and metformin use, wherein patients who were exposed to metformin had a low risk of developing cancer. Since then, various studies in DM2 patients have shown that metformin
metformin 10354 metformin had a low risk of developing cancer. Since then, various studies in DM2 patients have shown that metformin use is associated with a reduced risk of several cancers [2],[11],[74]-[79], including prostate cancer
metformin 10737 ovarian cancer [94]-[96] and hepatocellular carcinoma (HCC) [97],[98] (Table 4).Mechanisms of action of metformin and preclinical and ongoing studies in hematologic malignanciesTwo potential accepted antineoplastic
metformin 10862 and ongoing studies in hematologic malignanciesTwo potential accepted antineoplastic mechanisms of metformin have been proposed (Figure 2). First, metformin inhibits mitochondrial complex 1, resulting in low ATP
metformin 10910 malignanciesTwo potential accepted antineoplastic mechanisms of metformin have been proposed (Figure 2). First, metformin inhibits mitochondrial complex 1, resulting in low ATP production and an increase in the concentration
metformin 11697 downstream AKT/mTOR signaling and consequent suppression of cell proliferation [100],[101]. Second, metformin induces reductions in circulating insulin concentrations and IGF, preventing the activation of the insulin
metformin 12137 activity [104],[105].Despite the importance of LKB1 in the AMPK-dependent antineoplastic effects of metformin , this drug abolishes the increase in tumor growth linked with high-fat diet and hyperinsulinemia, irrespective
metformin 12548 mechanisms underlying tumor growth repression by dietary control [106]-[109].Many studies have shown that metformin synergizes with chemotherapeutic drugs at low doses, minimizing the side effects of high doses [99],[110],[111].
metformin 12750 doses [99],[110],[111]. More than 40 phase I/II clinical cancer trials (http://clinicaltrials.gov/) on metformin in combination with chemotherapeutics are underway worldwide. These studies are examining the antineoplastic
metformin 12880 chemotherapeutics are underway worldwide. These studies are examining the antineoplastic effects of metformin . This drug is used jointly with chemotherapeutic agents in cancers of the digestive (hepatic, gastric,
metformin 13143 systems (ovarian and endometrial) and lung, prostate, and breast cancer, and the clinical limitations of metformin in cancer treatment are being determined. Several trials have reported synergistic or additive effects
metformin 13442 studies have observed that these combinations are antagonistic in certain cancers [132]-[136]. Therefore, metformin synergizes with standard chemotherapy drugs to increase chemosensitivity in specific cancers.Cell metabolism
metformin 13772 and the availability of nutrients by altering their epigenetic and transcriptional programs. Notably, metformin is also involved in this cooperation between epigenetic and metabolic mechanisms. Du et al. [139] found
metformin 13891 involved in this cooperation between epigenetic and metabolic mechanisms. Du et al. [139] found that metformin decreases histone H2B (H2BK120) and monoubiquitination levels and inhibits the transcription of target
metformin 14249 p21 levels [140]. Further, the loss of the MM SET domain (MMSET) in MM cells [141] is regulated by metformin in prostate cancer cells [142]. Finally, metformin decreases the levels of a histone demethylase coactivator
metformin 14300 domain (MMSET) in MM cells [141] is regulated by metformin in prostate cancer cells [142]. Finally, metformin decreases the levels of a histone demethylase coactivator [143] and a metabolic enzyme in the TCA cycle
metformin 14438 histone demethylase coactivator [143] and a metabolic enzyme in the TCA cycle [144],[145].Myeloma and metformin AKT mediates the pathogenesis and progression of MM and resistance to standard treatments. Many upstream
metformin 14867 patients, especially in the advanced stages [105]. In accordance, in vitro and in vivo, the combination of metformin and dexamethasone synergizes to eliminate MM cells, inhibiting cell proliferation through reduced AKT/mTOR
metformin 15148 phosphorylation of TSC2 [147], which negatively regulates cell growth by acting upstream of mTOR [148].Notably, metformin inhibits glucose regulatory protein 78 (GRP78), an essential factor in bortezomib-induced autophagy
metformin 15357 and pharmacologically increases the anti-myeloma effects of bortezomib. Concomitant treatment with metformin and bortezomib inhibits the effects of the unfolded protein response (UPR) on GRO78, thus impairing
metformin 15657 xenotransplanted myeloma cells in vivo[149].The low toxicity and potent in vitro and in vivo effects of metformin , in combination with the findings of retrospective epidemiological studies in various cancer models,
metformin 15831 epidemiological studies in various cancer models, have prompted nearly 200 trials (ClinicalTrials.gov) examining metformin alone or in combination with other antitumoral agents in patients without diabetes. However, few studies
metformin 15977 antitumoral agents in patients without diabetes. However, few studies are determining the effects of metformin in MM (Table 5).Leukemias and metforminThe LKB1/AMPK/mTOR axis functions in hematopoietic cancers, such
metformin 16017 diabetes. However, few studies are determining the effects of metformin in MM (Table 5).Leukemias and metformin The LKB1/AMPK/mTOR axis functions in hematopoietic cancers, such as acute myeloid leukemia (AML) and
metformin 16177 cancers, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL); consequently, metformin represents a new perspective in hematological cancer therapy. Nevertheless, metformin does not appear
metformin 16263 consequently, metformin represents a new perspective in hematological cancer therapy. Nevertheless, metformin does not appear to alter the growth, differentiation, or survival of normal CD34+ stem cells [150]-[152].
metformin 16749 incidence of various tumors, including lymphomas, the development of which is significantly delayed by metformin [154]. Thus, metformin might increase the chemosensitivity of ALL through its inhibitory effects on
metformin 16772 tumors, including lymphomas, the development of which is significantly delayed by metformin [154]. Thus, metformin might increase the chemosensitivity of ALL through its inhibitory effects on the AKT/mTOR pathway via
metformin 17333 insulin and IGF-1 receptor (IGF-1R) on ALL blasts [157], a phenomenon that can be blocked through a metformin -mediated reduction in insulin levels.The PI3K/AKT/mTOR pathway is also stimulated by upstream oncogenes,
metformin 17711 pathogenesis of HTLV human retrovirus infection and adult T cell leukemia. Through the activation of AMPK, metformin suppresses the proliferation and clonogenic activity of several chronic myeloid leukemia (CML) lines,
metformin 17952 imatinib-resistant and T315I BCR-ABL mutants [152].In leukemic stem cells and stem cells of solid tumors, metformin is selective toward inducing death in vitro and tumor xenografts [159]. These findings are notable because
metformin 18236 treatment are one of the causes of neoplasia relapse [160].When combined with chemotherapy or other drugs, metformin might have additive effects on reducing cell growth and drug efflux through its activity on AMPK or
metformin 18413 through its activity on AMPK or P-glycoprotein [161],[162]. In acute promyelocytic leukemia (APL), metformin synergizes with trans-retinoic acid, inducing the differentiation and apoptosis in leukemic blasts [163].
metformin 18741 sensitivity to glucose deprivation; thus, the administration of the HIV protease inhibitor ritonavir and metformin to CLL cells has provided a strong rationale to target glucose metabolism and the ensuing metabolic
metformin 18942 metabolic plasticity in CLL [164].Based on these findings, future studies should examine the role of metformin in improving chemotherapy outcomes in ALL patients with or without diabetes. Many trials are testing
metformin 19053 in improving chemotherapy outcomes in ALL patients with or without diabetes. Many trials are testing metformin in patients without diabetes who have solid tumors. Four recent clinical trials (ClinicalTrials.gov)
metformin 19218 Four recent clinical trials (ClinicalTrials.gov) are measuring the clinical and biological outcomes of metformin combined with standard systemic chemotherapy in relapsed ALL (Table 6), and their findings will be reported
metformin 19354 systemic chemotherapy in relapsed ALL (Table 6), and their findings will be reported soon.Lymphoma and metformin Shi et al. [165] have provided the first evidence of the in vitro and in vivo activity of metformin in
metformin 19453 metforminShi et al. [165] have provided the first evidence of the in vitro and in vivo activity of metformin in human lymphoma cells, demonstrating that the activity of drug on AMPK inhibits the growth of B and
metformin 19796 doxorubicin and temsirolimus, a mTOR inhibitor, is significantly improves upon coadministration with metformin . In addition to inhibiting the mTOR pathway, metformin activates p53 by suppressing murine double minute
metformin 19851 significantly improves upon coadministration with metformin. In addition to inhibiting the mTOR pathway, metformin activates p53 by suppressing murine double minute X (MDMX), thereby causing apoptosis [166].Rosilio
metformin 19992 murine double minute X (MDMX), thereby causing apoptosis [166].Rosilio et al. [167] demonstrated that metformin , phenformin, and AICAR, an AMPK activator, have robust antitumor activities against human T-LEN and
metformin 20524 factor-1 receptor (IGF-1R)] are overexpressed in Peripheral T-cell lymphomas (PTCL), supporting the use of metformin as an inhibitor of mTORC2 and NF-κB in PTCL [168].In diffuse large B cell lymphoma (DLBCL) patients
metformin 20650 of mTORC2 and NF-κB in PTCL [168].In diffuse large B cell lymphoma (DLBCL) patients with diabetes, metformin , as a first-line chemoimmunotherapeutic agent with rituximab, improved progression-free survival (PFS;
metformin 21058 retrospective trial, only four ongoing clinical trials (ClinicalTrials.gov) are evaluating the effects of metformin with standard systemic chemotherapy in the settings of relapsed and refractory NHL (Table 6).The combined
metformin 21572 opportunities. In conjunction with interdisciplinary research, epidemiological and preclinical data support that metformin benefits select patients with solid tumors and hematological tumors; however, strict clinical trials
metformin 21740 hematological tumors; however, strict clinical trials are required to pinpoint patients who might benefit from metformin combinations. Thus, we need to assess whether the anticancer effects of metformin depend on metabolic
metformin 21822 might benefit from metformin combinations. Thus, we need to assess whether the anticancer effects of metformin depend on metabolic variables, such as diabetes, BMI, insulin resistance, and obesity-related inflammation.AUTHOR
metformin 22321 effects) and AMPK-dependent molecular mechanisms (direct effects) underlying the anticancer effects of metformin . AMPK activation in the liver results in decreased insulin and IGF-1 levels and consequent attenuated
metformin 22771 (IRS1) and the activation of regulated in development and DNA damage response 1 (REDD1). In addition, metformin -induced activation of AMPK leads to the phosphorylation of p53, inducing cycle arrest, apoptosis and
metformin 26277 observational and case-control studies on the risk of cancer in organs of patients with diabetes treated with metformin .Type of cancer (author and year)Type of study and patient cohortRR, HR or OR (95% CI)*Several (Evans
metformin 27359 carcinoma 1.82 (0.85-3.91)Lung (Lin et al. 2015) ([83])Retrospective observational/750HR in favor of metformin use EC IV 0.80 (0.71-0.89)Lung (Zhu et al. 2015) ([45])Meta-analysis of 8 studies/17.997RR 0.84 (0.73-0.97)HNC*
metformin 27729 (Yen et al., 2014) ([85])Retrospective observational/290The incidence of CCP was 0.64x lower in the metformin group (pcts>65a had lower risk reduction of CCP)Breast (Col et al. 2012) ([86])Meta-analysis of 7 studies/17.997OR
metformin 29210 11 studies/3452OR prevention 0.38 (0.24-0.59)*DM: diabetes mellitus, HNC: head and neck cancer, met: metformin , pCR: pathologic complete response, HR: hazard ratio, OR: odds ratio, OS: Overall survival, RR: relative
metformin 29367 ratio, OR: odds ratio, OS: Overall survival, RR: relative risk.Table 5Ongoing clinical studies with metformin in MM.Type of diseaseDisease statusType of studyAssociated drugsCountry of studyClinicalTrials.gov identifierMM*
metformin 29755 lymphocytic leukemia, USA: United States of America, BR: Brazil.Table 6Ongoing clinical studies with metformin in leukemias and lymphomas.Type of diseaseDisease statusType of studyAssociated drugsCountry of studyClinicalTrials.gov
prednisone 30614 AML: acute myeloid leukemia, CLL: chronic lymphocytic leukemia, DA-EPOCHR: dose-adjusted etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin + rituximab, MM: multiple myeloma, NHL: non-Hodgkin lymphoma,
prednisone 30839 DLBCL: diffuse large B cell lymphoma, R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone , USA: United States of America
Select Disease Character Offset Disease Term Instance
diabetes mellitus 201 Barreto Campello CarvalheiraPublication date (epub): 8/2018Publication date (ppub): /2018AbstractType 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated
diabetes mellitus 417 upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus . Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can
diabetes mellitus 1395 malignancies.INTRODUCTIONBased on the increasing incidence of cancer along with increasing rates of obesity and type 2 diabetes mellitus (DM2), much effort has been made to identify the epidemiological and biological connections between
diabetes mellitus 5794 is increasing worldwide, MM, leukemia, and NHL are being diagnosed more frequently with concomitant diabetes mellitus [9],[48],[51]-[53]. Therefore, physicians who treat patients with these comorbidities must consider
diabetes mellitus 29159 (0.24-0.59)Liver (Ma et al. 2012) ([98])Meta-analysis of 11 studies/3452OR prevention 0.38 (0.24-0.59)*DM: diabetes mellitus , HNC: head and neck cancer, met: metformin, pCR: pathologic complete response, HR: hazard ratio, OR:
hyperglycemia 3169 several conditions, such as hyperinsulinemia (due to resistance to endogenous or exogenous insulin), hyperglycemia , and chronic inflammation due to overweight and body fat mass [10],[12].Adiposity has been correlated
hyperinsulinemia 3096 especially obesity [12], and DM2 and malignancies are correlated through several conditions, such as hyperinsulinemia (due to resistance to endogenous or exogenous insulin), hyperglycemia, and chronic inflammation due
hyperinsulinemia 12227 effects of metformin, this drug abolishes the increase in tumor growth linked with high-fat diet and hyperinsulinemia , irrespective of LKB1 expression by the tumor. This antineoplastic activity is connected with decreased
obesity 1376 malignancies.INTRODUCTIONBased on the increasing incidence of cancer along with increasing rates of obesity and type 2 diabetes mellitus (DM2), much effort has been made to identify the epidemiological and biological
obesity 1658 are gradually being required to tailor cancer treatments for patients with pre-existing diabetes or obesity , and endocrinologists often need to control diabetes in patients who are undergoing treatments for cancer
obesity 3006 that link diabetes and cancer [10],[12]. Notably, DM2 and cancer share many risk factors, especially obesity [12], and DM2 and malignancies are correlated through several conditions, such as hyperinsulinemia (due
obesity 3870 gammopathy of uncertain significance (MGUS) transforming into MM [3],[6]-[8],[3]-[26].Mechanistically, obesity —a state of excess nutrient levels—chronically activates signaling pathways that upregulate insulin,
obesity 21214 settings of relapsed and refractory NHL (Table 6).The combined increase in the occurrence of diabetes, obesity , and cancer has created a significant problem in which complex disease pathophysiologies are intertwined.
obesity 21910 effects of metformin depend on metabolic variables, such as diabetes, BMI, insulin resistance, and obesity -related inflammation.AUTHOR CONTRIBUTIONSCunha Júnior AD and Pericole FV wrote the initial drafts of
obesity 23179 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase.Table 1Relative risks associated with overweight and obesity and percentage of cases attributable to overweight and obesity in the United States, the European Union,
obesity 23242 risks associated with overweight and obesity and percentage of cases attributable to overweight and obesity in the United States, the European Union, and Brazil.Type of cancerRR* BMI 25-30 kg/m2RR* BMI>30 kg/m2FAP*
obesity 24901 1.25-1.54) for obese individuals (BMI >or= 30 kg/m(2)); a total of 9 cohort studies with data on BMI or obesity in relation to the incidence of leukemia were included (6).Subtypes of leukemiaMeta-analysis: RRs associated
obesity 25023 the incidence of leukemia were included (6).Subtypes of leukemiaMeta-analysis: RRs associated with obesity were 1.25 (95% CI, 1.11-1.41) for CLL, 1.65 (95% CI, 1.16-2.35) for ALL, 1.52 (95% CI, 1.19-1.95) for
type 2 diabetes mellitus 410 upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus . Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can
type 2 diabetes mellitus 1388 malignancies.INTRODUCTIONBased on the increasing incidence of cancer along with increasing rates of obesity and type 2 diabetes mellitus (DM2), much effort has been made to identify the epidemiological and biological connections between

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