Metformin as a therapeutic tool for resistant hematological malignancies: a literature review

Introduction

Cancer is a worldwide public health problem responsible for 10 million deaths in 2020, corresponding to one in six deaths in the world (1). According to origin, cancers can be classified as hematological or solid neoplasms (2). HMs are a group of neoplasms associated with an uncontrolled growth of hematopoietic and lymphoid tissues, due to the loss of normal hematopoietic function (3,4). HMs are responsible for 1.2 million cases per year in the world and correspond to 7% of diagnosed cancers (5), which are generally divided into three types: leukemia, lymphoma, and multiple myeloma (MM) (6). HMs treatment evolved over the years and currently involves chemotherapy, targeted therapies, immunotherapies, chimeric antigen receptor T-cells (CAR-T cells), radiotherapy, and hematopoietic stem cell transplant (HSCT) (5,7). Despite the evolution of the treatment and prognostic of HMs patients, many patients deal with treatment resistance and recurrence (5). The loss of treatment efficiency is linked to cell adaptations for survival, which involves mutations and modulation of cell processes, such as apoptosis, autophagy, proliferation, and metabolism (5). Another important tool for HMs resistance/relapse is CSCs, mainly for leukemias and MM (7,8). Therefore, new therapeutic strategies are necessary to overcome the treatment failure.

Metformin is a biguanide drug and an anti-hyperglycemic agent, approved by U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus (T2DM) in 1994, being considered the first-line treatment for T2DM due to its efficacy (9,10). In addition to being an anti-diabetic drug, studies have shown the action of metformin in multiple pathways in cancer, highlighting its potential use in the treatment of different types of cancer, including lung (11,12), breast (13,14), colorectal (15,16) and ovarian cancer (17). The number of studies that have been evaluating metformin use in the therapy of HMs is increasing, highlighting its capacity to overcome drug resistance in HMs (18-20). In this paper the antitumoral mechanisms of metformin will be reviewed and its potential application on resistant HMs will be discussed. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-23-157/rc).

Methods

We performed a literature review using PubMed to understand metformin’s action in cancer and evaluate its potential application in HMs, including in resistant, relapse, and refractory diseases. Studies published between 1996 and 2023 were considered for this review. To explore metformin use in clinical, clinical trials submitted to clinicaltrials.gov about metformin use in resistant/relapse/refractory HMs were considered. Only studies published in English were evaluated (Table 1).

Metformin and its antitumoral mechanisms of action

Metformin is a biguanide drug, first synthesized in 1922 by Werner & Bell from a plant called Galega officinalis (21). Associated with its anti-hyperglycemic action, low cost, and tolerance (low risk of lactic acidosis), metformin is considered the first-line therapy for T2DM patients (22). In 2005, Evans et al. published an innovative study, that highlighted for the first time the potential antitumoral effects of metformin by the demonstration that T2DM patients under metformin use have a lower risk of developing cancer compared to other diabetic patients that not used metformin (23). This study opened new ways for the use of metformin, motivating the scientific community to investigate the role of metformin in cancer. Nowadays, metformin is known as a potential antitumoral drug, acting in different kinds of cancer and under investigation in 440 cancer clinical trials, including in hematological tumors.

Metformin is a hydrophilic and cation drug on physiological pH, requiring transporters to cross cell membranes, such as solute carrier organic transporters, enabling its action in cells (24). The main transporters involved with metformin transport are (I) the plasma membrane monoamine transporter (PMAT), (II) organic cation transporters (OCTs) 1–3 and, (III) the multidrug and toxin extrusion 1–2 (MATE 1/2) (24,25); PMAT and OCT1 mediates the gastrointestinal uptake of metformin. Once in the bloodstream, OCT1 promotes hepatic uptake and OCT3 is important for muscle uptake (24). As metformin is not metabolized, its excretion depends on kidney elimination, for this metformin enters the kidney through OCT2 and is excreted in urine by MATE 1/2 (24). The transport of metformin is essential for its mechanisms of action in cancer cells, which is generally divided into indirect (related to metformin’s anti-hyperglycemic effect) and direct effects.

Indirect effects

Metformin could exert its anti-cancer action through its anti-diabetic effects, which are associated with the reduction of blood glucose and insulinemia, important factors in tumorigenesis. Metformin improves insulin sensitivity, reducing insulinemia and insulin growth factor-1 (IGF-1), which promotes cancer progression (26). Associated with the reduction of insulin levels, the inhibition of hepatic glucose production, and the higher uptake of glucose by skeletal muscle, the drug reduces blood glucose (26) (Figure 1). Through the reduction of blood glucose and insulin levels, metformin impairs inflammation and the activation of the phosphatidylinositol-3-kinase/Akt and mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, important to tumorigenesis (9).

Figure 1 Metformin and its indirect effects in cancer. Metformin through its action as an antidiabetic drug can improve insulin sensitivity, reduce insulinemia, inhibit hepatic gluconeogenesis, and increase glucose uptake by skeletal muscle, promoting the reduction of blood glucose levels and thus impairing tumorigenesis.

Direct effects (tumor cell metabolism)

Metformin acts through modulation of tumor cell energetic metabolism, mainly through adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation (9). In 2000, Leverve group discovered that metformin inhibits the complex I (CI) of the electron transport chain (ETC), impairing the electron flow throughout the ETC, reducing NADH oxidation (enhancing NADH/NAD ratio), leading to the loss of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, impairment of oxidative phosphorylation (OXPHOS), diminishing oxygen consumption and decreasing adenosine triphosphate (ATP) levels, which increases the AMP/ATP or adenosine diphosphate (ADP)/ATP ratio (27,28). The most acceptable explanation for metformin action in mitochondria is related to the positive charge of the drug, enabling its interaction with the MMP, drug accumulation in the mitochondrial matrix, and its action (29,30). Different from its similar, rotenone which is an irreversible inhibitor of CI, metformin is known as a reversible inhibitor (29).

As a result of ATP depletion, metformin activates AMPK to restore energy homeostasis, leading to a change from anabolic to catabolic status, impairing the synthesis of proteins, lipids, and nucleotides, important for cancer growth (3,22). Although AMPK is directly activated as a consequence of ATP depletion, AMPK can be activated indirectly by the liver kinase B1 (LKB1), an upstream kinase that promotes AMPK activation through the phosphorylation of alpha (α) AMPK subunit, and through lysosomal pathway, where metformin binds to presenilin enhancer-2 (PEN2), making a complex that interacts with ATP6AP1 (V-ATPase subunit), inhibiting V-ATPase and activating AMPK (31,32). Consequently through AMPK activation, occurs: (I) the inhibition of mTOR, which mediates protein synthesis and cancer growth (33,34), (II) activation of p53, mediating cell cycle arrest, autophagy and apoptosis (35,36), (III) inactivation of acetyl-CoA carboxylase (ACC), reducing lipogenesis (37,38) and (IV) inhibition of adenylate cyclase (AC), histone deacetylase (HDAC) and CREB-regulated transcription coactivator 2 (CRTC2), which are involved with the reduction of gluconeogenesis genes transcription (22).

Associated with the increase of NADH/NAD ratio, metformin reduces the tricarboxylic acid (TCA) cycle and its intermediates (39), which are used for cancer cells to energy production and macromolecule biosynthesis (40). Therefore, through AMPK activation, metformin impairs the energetic metabolism of cancer cells and the biosynthesis of macromolecules, processes that are essential for cancer progression.

Independent of AMPK activation, metformin inhibits the mitochondrial glycerol-3-phosphate (G3P) dehydrogenase (mGPDH), that forms with its cytosolic version the glycerol-phosphate shuttle (41). mGPDH acts in the oxidation of G3P to dihydroxyacetone phosphate (DAP) associated with the reduction of FAD to FADH2, transferring the electrons to coenzyme Q of ETC, helping the maintenance of MMP and thus the ETC function (42). Through this inhibition, occurs the reduction of gluconeogenesis from glycerol and the increase of NADH/NAD ratio (43) (Figure 2).

Figure 2 Metformin and its molecular mechanisms of action in cancer. Metformin enters cells through transporters, like OCTs, leading to its accumulation in the mitochondria matrix and inhibition of complex I of the ETC (enhancing NADH/NAD+ ratio) and mGPDH, inducing the loss of MMP, ROS production, impairment of OXPHOS and reducing ATP levels. Associated with the decrease of ATP levels, metformin activates AMPK to restore energy homeostasis. The AMPK activation can also occur through LKB1, an upstream kinase that promotes its phosphorylation, and by the lysosomal pathway, where metformin binds to PEN2, making a complex with ATP6AP1, promoting V-ATPase inhibition and AMPK activation. As a result of AMPK activation, occurs: the inhibition of mTOR (decreasing protein synthesis and cancer growth), ACC (reducing lipogenesis) and of AC, HDAC and CRTC2 (decreasing the transcription of gluconeogenesis genes); beyond the activation of p53, leading to cell cycle arrest, autophagy and apoptosis. Linked to the increase of NADH/NAD+ ratio, metformin impairs the TCA cycle, decreasing its intermediates, which are important for macromolecule synthesis and thus for cancer progression. OCTs, organic cation transporters; ETC, electron transport chain; mGPDH, mitochondrial glycerol-3-phosphate dehydrogenase; MMP, mitochondrial membrane potential; ROS, reactive oxygen species; OXPHOS, oxidative phosphorylation; AMPK, adenosine monophosphate-activated protein kinase; LKB1, liver kinase B1; PEN2, presenilin enhancer-2; ATP6AP1, V-ATPase subunit; mTOR, mammalian target of rapamycin; ACC, acetyl-CoA carboxylase; AC, adenylate cyclase; HDAC, histone deacetylase; CRTC2, CREB-regulated transcription coactivator 2; TCA, tricarboxylic acid.

Another important effect of metformin is its action in CSCs. CSCs are a group of cancer cells with unlimited self-renewal capacity, frequently linked to tumor recurrence, resistance to treatment, and metastasis, because many antitumoral treatments are unable to kill CSCs (44). Despite this, there is an increasing number of studies that demonstrate the capacity of metformin to inhibit CSCs in different cancers, including gastric (45), breast (46), and ovarian (47) cancers. Through its action in CSCs, metformin can be a tool for avoiding cancer resistance and metastasis, which are recurring problems among oncology patients and the main causes of treatment failure and cancer deaths (48) (Figure 3).

Figure 3 Metformin and CSCs. CSCs are a group of cancer cells with self-renewal capacity and associated with a higher activation of PI3K/Akt/mTOR pathway, possibly its relationship with tumor recurrence, resistance to treatment, and metastasis, resulting in treatment failure and deaths. As shown by a study, metformin can kill CSCs in different cancers, which can be caused through AMPK activation and mTOR inhibition by metformin (44). Purposing metformin as a tool to overcome treatment failure and reduce cancer deaths. CSCs, cancer stem cells; PI3K/Akt/mTOR, phosphatidylinositol-3-kinase/Akt and mammalian target of rapamycin; AMPK, adenosine monophosphate-activated protein kinase.

Linked to metformin’s antitumoral properties, metformin is being used with other cancer treatments to achieve a synergistic effect (49-51), beyond its use in the resensitization of drugs, being able to reverse resistance cases (52,53).

Metformin as a therapeutic approach for resistant hematological tumors

HMs consist of a group of tumors with hematopoietic origin and are currently divided into leukemias, lymphomas, and MM (54,55). Despite the available therapeutic approaches’ efficiency, many HMs become resistant to therapy in distinct ways, considered an important obstacle to a successful treatment (56,57). The resistance can be intrinsic, when the cells are resistant before the treatment, or acquired, characterized by the cells’ acquisition of resistance during the therapy (57-60). Beyond that, the causes of cancer resistance to therapy are classified as host factors, tumor factors, and tumor-host interactions (59). The resistance related to host factors, includes: (I) patient’s genetics and habits, (II) genetic variants, and (III) drug-drug interactions (DDIs) (60-64). Tumor factors refer to alterations in the drug targets (65-67), diminished drug concentration inside the cell (68-74), impairment of the regulation of cell death pathways (75-77), enhanced of DNA repair mechanisms (78,79), epigenetic modifications (80,81), intratumoral heterogeneity (82) and CSCs (83). The interaction between tumor and its microenvironment (TME) and low pH TME are elements linked to resistance caused by tumor-host interactions (60,84). Given this scenario of HMs resistance, new therapeutic approaches are necessary. Below, the potential use of metformin in different resistant HMs will be presented.

Leukemias

Leukemia is a malignancy resulting from the dysregulated proliferation of leukocytes. This malignancy is classified as acute or chronic, according to its proliferation profile, and in myeloid or lymphoid, related to the cell origination. This classification divided leukemias into four types: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphoblastic leukemia (CLL) (85). Leukemia is responsible for 2.5% of the diagnosed cancers, affecting approximately 400,000 people per year (5).

CML

CML is a malignant hematological disorder cytogenetically characterized by the Philadelphia (Ph) chromosome, formed through a reciprocal translocation between the chromosomes 9 and 22, t(9;22) (q34;q11), resulting in the formation of BCR-ABL1 oncogene (86,87). This oncogene promotes the activation of the tyrosine kinase pathway, an important step for leukemogenesis (88). Worldwide, CML had an incidence rate nearly of 1 per 100,000 people in 2018, making CML responsible for around 15% of leukemia cases in adults (89). This incidence rate increases among older people, as the median age of diagnosis is 56 years old (90). The available therapies for CML involve chemotherapy, immunotherapy by interferon-alpha (IFN-α), stem cell transplant, and tyrosine kinase inhibitors (TKIs) (91). The use of TKIs revolutionized CML treatment, so that imatinib (first-generation TKI) is used as first-line therapy for CML due to its efficiency (92). Although its action, around 10% of patients develop resistance to imatinib, for these patients second-(dasatinib, nilotinib, bosutinib, and radotinib) and third-generation TKIs as ponatinib can be employed (92-95). The main cause of imatinib resistance is point mutations in BCR-ABL1 oncogene, among these mutations, T315I is considered the most challenging, and only the third-generation TKI, ponatinib can act against this mutation (92,96). Despite ponatinib action, the use of this TKI can result in cardiovascular thrombotic events (97). This scenario evidences the importance of new therapies to treat resistant CML, especially to overcome the T315I mutation.

The achievement of complete cytogenetic response (CcyR), characterized by less than 1% Ph chromosome-positive cells, is an important step to avoid relapse (98), but only 66–88% of patients achieve CcyR after one year under TKI treatment (Table 2) (99). Pokorny et al. developed a clinical trial where 59 CML patients were divided into two groups: the metformin group (TKI and metformin concomitant use—5 patients) and the non-metformin group (54 patients—TKI therapy alone). The metformin group achieved 100% CcyR against 73.6% in the non-metformin group. In relation to major molecular response (MMR; BCR-ABL gene in blood or bone marrow is 1/1,000 or less) and complete molecular response (CMR; BCR-ABL gene is not present), the median time to achieve these parameters was 11.1 months in metformin group and 19.5 months in non-metformin group for MMR, and 37.4 months for CMR in metformin group (in non-metformin group CMR was not observed) (Table 2) (99). This study indicates that the concomitant use of metformin and TKIs enhances treatment success, increasing the chance of CcyR and reducing the time to achieve MMR and CMR, important factors to avoid a relapse/treatment failure.

The resistance to imatinib is increasing and overcoming this scenario is a challenge. In this context, Vakana et al. showed for the first time the capacity of metformin to act against cell lines positive for Ph chromosome and primary leukemic cells of CML patients, including those harboring T315I-BCR-ABL mutation (Table 2) (100). Due to the potential antileukemic effect of metformin, Shi et al. analyzed if metformin was able to restore the imatinib effect in the imatinib-resistant CML cell line (K562R). In this study, K562R cells were more sensitive to metformin than its parental cell line (K562) and the metformin + imatinib combination promoted a better inhibition of proliferation and cell viability than imatinib alone. Metformin also resensitized K562R cells to imatinib (Table 2) (101) (Figure 4A).

Figure 4 Metformin action in resistant leukemias. (A) In CML, metformin was able to: (I) act against cells harboring T315I mutation (linked to imatinib resistance) and resensitize CML-resistant cells to imatinib, (II) impair P-gp overexpression, sensitizing MDR CML cells to imatinib and (III) reduce p-JNK, resensitizing CML cells to nilotinib. (B) In AML, FLT3-ITD mutation is a marker of relapse and to act against this mutation is used sorafenib, however, resistance cases can occur; in this context, metformin enhanced sorafenib effect in FLT3-AML cells, possibly overcome sorafenib resistance. Resistance to cytarabine is also an important problem in AML, which can be overcome by metformin through the inhibition of the mTORC1/P70S6K pathway and blocking the mitochondrial transfer between stromal and AML cells, sensitizing AML cells to cytarabine. (C) Modulation of metabolism is an important tool for CLL, to enhance treatment effectiveness and overcome resistance, metformin was able to reduce OCR and ECAR, indicating the impairment of OXPHOS and glycolysis, impacting cancer metabolism and sensitizing CLL cells to ritonavir. (D) A common marker of treatment failure in ALL is the Bcl-2 and ABCB1 gene overexpression, in this context, metformin was able to act against these factors in vitro and in clinical trials, acting as an adjuvant to ALL therapy. CML, chronic myeloid leukemia; P-gp, permeability glycoprotein; MDR, multidrug resistance; JNK, jun kinase; p-JNK, JNK phosphorylation; FLT3-ITD, fms-like tyrosine kinase 3-internal tandem duplication; AML, acute myeloid leukemia; mTORC1, mammalian target of rapamycin complex 1; CLL, chronic lymphocytic leukemia; OCR, oxygen consumption rate; ECAR, extracellular acidification rate; OXPHOS, oxidative phosphorylation; ALL, acute lymphoblastic leukemia; ABCB1, ATP binding cassette subfamily B member 1.

Multidrug resistance (MDR) is a factor responsible for treatment failure and the expression of P-glycoprotein (P-gp) is often related to MDR. P-gp is an ATP-dependent efflux pump that mediates the drug transport to the cell outside, reducing drug concentration inside the cell (108). Curvello et al. demonstrated that metformin acts against the MDR CML cell line (K562-Lucena) and enhances imatinib cytotoxicity when in combination, probably by the reduction of P-gp expression (Table 2) (102) (Figure 4A).

Aiming to find an alternative for imatinib-resistant CML, Glamoclija et al. showed that metformin and thymoquinone (TQ), both at monotherapy and combination therapy, reduced the viability and proliferation and promoted apoptosis of CML cells, including those resistant to imatinib. Highlighting a stronger effect of the combination in reducing proliferation and apoptosis of imatinib-resistant CML cells (Table 2) (103). Indicating metformin and TQ combination as an alternative therapy in the context of imatinib resistance.

Although imatinib is considered the first-line therapy for CML, the second-generation TKI nilotinib, has a similar action to imatinib and a stronger effect both in imatinib-sensitive and -resistant CML patients, possibly its use in CML treatment (Table 2) (104). Despite nilotinib efficiency, the number of resistance cases is increasing and needs attention (109,110). Na et al. showed for the first time that jun kinase (JNK) overexpression is related to nilotinib resistance in CML cell lines. As metformin is a known regulator of JNK pathway, the study demonstrated the reduction of the JNK phosphorylation in nilotinib-sensitive and resistant cells by metformin, resensitizing cells to nilotinib (Figure 4A). Metformin also enhances nilotinib cytotoxicity through the lower expression of the anti-apoptotic protein Bcl-Xl (Table 2) (104).

Vincristine chemotherapy is an approach used to treat leukemias, including CML. Despite this, its toxicity and resistance are common problems related to vincristine use (105). Yi et al. showed that metformin sensitizes leukemia cells (K562-CML and A301-ALL) to vincristine, enhancing apoptosis in an AMPK-dependent manner (Table 2) (105). This study proposes metformin as an adjuvant therapy to vincristine in leukemia treatment.

CML leukemia stem cells (LSCs) are considered the progenitors of CML cells, responsible for the chronic phase of CML and its recurrence (111). CML LSCs are resistant to TKIs, including imatinib, nilotinib, and dasatinib, so that 50% of relapse CML patients are linked to LSCs action (7,112). Due to that, drugs that can act in LSCs are promising candidates to avoid CML recurrence. As demonstrated by different studies, metformin inhibits CSCs in many cancers, including in AML (113). Purposing metformin as a therapeutic approach to act against LSCs, possibly the reduction of CML recurrence and the enhancement of survival.

AML

AML is the main leukemia type among adults, being responsible for 80% of leukemia cases. It is caused by a clonal expansion of immature blast cells in the peripheral blood and bone marrow (114). Due to the treatment evolution, involving chemotherapy, HSCT, immunotherapy, and target therapy, the number of AML patients that achieve complete remission (CR) is increasing (115). The first-line therapy for AML is the combination of daunorubicin (DA)/idarubicin (IDA) with cytosine arabinoside (cytarabine, Ara-C), with a CR rate of 60–80% in young adults and 40–60% in older adults (>65 years old) (115-117). Despite therapy evolution and the efficiency of the first-line treatment, many patients failed therapy and relapsed after CR, mainly among older people (19,115) (Table 3). The treatment failure is often related to drug resistance, which can be caused by distinct resistant mechanisms, as (I) drug resistance-related protein and enzyme, like P-gp and multidrug resistance-related protein (MRP1) that reduces drug accumulation in the cell; (II) genetic modifications; (III) miRNAs alterations in drug resistance and (IV) extensive activation of drug resistance-related signal pathway, like PI3K/Akt (115).

The mutation of fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) found in 30% of AML patients is associated with poor prognosis and is considered a relapse-related genetic marker (Table 3) (118). To treat FLT3-ITD AML is used sorafenib, a kinase inhibitor that acts against FLT3 (121). Although its efficiency in FLT3-AML, sorafenib use as monotherapy can cause resistance (Table 3) (118). Wang et al. showed that metformin acts on FLT3-ITD AML cells and synergistically increases the sorafenib effect through the inhibition of mTOR and promotion of apoptosis and autophagy of these cells (Table 3) (118). Therefore, metformin potentializes the anti-FLT3-ITD AML effect of sorafenib, possibly overcoming sorafenib resistance in FLT3 AML cells (Figure 4B).

Cytarabine has been used as the first-line treatment for AML since 1973, despite its efficiency with high CR rates, many patients relapse and 80% of them do not have an efficient alternative therapy, leading to death (122). Yuan et al. demonstrated an improvement of cytarabine anti-AML effect through inhibition of mTORC1/P70S6K pathway by metformin, leading to cell cycle arrest in S phase in vitro and showed a similar synergetic effect with cytarabine in AML mice (Table 3) (119) (Figure 4B). By potentializing the cytarabine effect, metformin constitutes a promising therapy to overcome that resistance and thus enhance the survival of AML patients.

Bone marrow microenvironment (BMME) is essential for AML cells and is related to drug resistance, enhancing relapse cases (123,124). The BMME-relapse cases are associated with the mitochondrial transfer from stromal cells to AML cells in bone marrow, which was already observed in other HMs, including AML, ALL, and MM (125-127), an interaction that mediates chemoresistance and relapse. In view of disrupting this interaction, You et al. showed that this interaction and mitochondria transfer between stromal cells and AML cells occurs both in vitro and in vivo, and was responsible for cytarabine resistance. When metformin was applied, AML cells turned sensitive to cytarabine due to the inhibition of mitochondrial transfer between stromal and AML cells, in vitro. A similar effect was observed in vivo, where metformin increases Ara-C anti-AML action by disrupting the interaction of BMME and AML cells (Table 3) (19). Thus, blocking mitochondrial transfer from stromal BM to AML cells, as done by metformin, is a potential mechanism to overcome chemotherapy resistance (Figure 4B).

P-gp and MRP1 are ATP-binding cassette (ABC) transporter proteins frequently associated with AML resistance through the decrease of drug concentration in cells (128). Possibly due to the decrease of ATP content, metformin can reduce the expression of P-gp and MRP1, as showed in some types of cancer (129-131). Beyond its action on ABC transporters, metformin as a metabolic disruptor can reduce the activation of the PI3K/Akt pathway in cancer (132). Considering the importance of ABC transporters and PI3K/Akt pathway for AML resistance, which are targets of metformin, evaluating the action of metformin in these factors can be a potential way to overcome AML resistance by metformin.

LSCs can be responsible for chemotherapy resistance in AML. Studies have shown that therapy-resistant leukemia cells, known as minimal residual disease (MRD) in LSCs are currently related to resistance cases (133). Therefore, there are necessary therapies that can eliminate these cells. As shown in other studies, metformin can kill CSCs, like AML CSCs (113). Thus, metformin’s possible contribution to eliminating MRD-LSCs needs investigation.

Linked to the potential use of metformin in resistant AML, a phase 2 clinical trial (NCT05854966) is on course to evaluate its effects with CPI-613 in relapsed/refractory AML (Table 4). Highlighting metformin as a tool to overcome AML drug resistance.

CLL

CLL is an adult leukemia, characterized by a higher accumulation of dysfunctional lymphocytes in blood, bone marrow, lymph nodes, and spleen (134). In Western countries, CLL represents 25–30% of leukemia cases (135), being responsible for more than 40,000 deaths and with an average incidence of 100,000 cases in 2019, worldwide (134). CLL generally affects elderly people, with a median age of 70 years old, beyond that CLL has an incidence two times higher in men than in women (136-138).

CLL treatment currently involves targeted drugs, including venetoclax (Bcl-2 inhibitor) and bruton tyrosine kinase inhibitors (BTK), like ibrutinib and zanubrutinib (139-142). Although treatment evolution and efficiency, the development of drug resistance and relapse are increasing, making this disease considered incurable (143). Genetic alterations have an important contribution to CLL relapses, deletions of TP53 and ataxia telangiectasia mutated (ATM) at the 17p13 and 11q22-q23 chromosomal regions are frequently found in relapsed/refractory patients (144). In this context, new drugs are necessary to improve CLL survival.

Targeting cancer metabolism and its adaptations are very important in anti-tumoral therapy, such as for CLL treatment. Adekola et al. showed that the combination of metformin (CI inhibitor) and ritonavir (GLUT4 inhibitor) affects CLL viability, reducing oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), indicating impairment of OXPHOS and glycolysis, and thus of CLL metabolism (106) (Table 2). Showing metformin + ritonavir combination as an alternative therapy to CLL. In the study of Bruno et al., metformin was shown as a cytotoxicity agent for CLL and potentialized fludarabine and ABT-737 action in CLL cells (107) (Table 2). Purposing metformin as a potential alternative therapy for CLL, both in monotherapy and combination therapy (Figure 4C).

Currently, two clinical trials are on course associated with the use of metformin in relapsed CLL. One is a phase 1 study of the combination therapy between metformin and ritonavir in relapsed/refractory CLL (NCT02948283), and the other is a phase 2 study about the use of metformin in relapsed or untreated CLL (NCT01750567) (Table 4).

ALL

ALL is characterized by an uncontrolled proliferation of lymphocytes, which can disseminate to bone marrow, blood, and extramedullary sites (145). This leukemia occurs mainly in children, with a high incidence between 1–4 years old, so the probability of developing ALL tends to fall with increasing age (145). In the USA, nearly 5,960 ALL cases were diagnosed, and 1,470 deaths were registered in 2018 (145,146). Although the treatment advances, with an increase of 5-year overall survival, in adults with 50 years old or more, just 25% of them live for 5 years after the diagnosis (147-149). The treatment of ALL involves four steps: induction, which involves glucocorticoid, vincristine, L-asparaginase and anthracycline; consolidation, with cytarabine, methotrexate, vincristine, asparaginase, mercaptopurine and glucocorticoids; intensification (like induction) and maintenance, which involves mercaptopurine, methotrexate, vincristine and glucocorticoids (145). Despite the treatment advances, the rate of successfully therapy in adults is 30–40%, while in children is nearly 90% (150,151). This lower cure rate in adults adding to the resistant ALL cases indicates the necessity of new therapeutical approaches.

Bcl-2 overexpression in ALL is commonly related to drug resistance (152-156), therefore Rodríguez-Lirio et al. showed that metformin promotes cell cycle arrest and apoptosis in 10E1-CEM cells, harboring Bcl-2 overexpression and drug resistance (120) (Figure 4D) (Table 3). Another important factor for ALL resistance and lower survival is the overexpression of the ABCB1 gene (Pgp encoder), mediating drug extrusion and lower accumulation in cells (157-159). In a clinical trial (NCT03118128) with 102 ALL patients, divided into metformin users (n=26, receiving metformin + prednisone) and metformin non-users (n=76, in prednisone treatment), Ramos-Peñafiel et al. demonstrated metformin as a protective agent against drug failure and relapse in ALL patients with high ABCB1 expression, leading to an increase of the patient’s survival (18) (Figure 4D). In a clinical trial by Trucco et al. (NCT01324180) with 14 relapsed/refractory ALL patients (only 9 patients were evaluated), metformin was used with vincristine, dexamethasone, PEG-asparaginase, and doxorubicin (VXLD) for 28 days and was able to induce 5 CR, 1 partial response and 1 stable disease (160). Indicating metformin as an adjuvant therapy in resistant ALL (Table 4).

Associated with the importance of AMPK gene expression for antitumoral effects and the relationship between the ABCB1 gene and drug resistance in ALL, a clinical trial (NCT05326984) with adolescents harboring ALL is on a recruiting stage to evaluate the capacity of metformin added to standard induction remission chemotherapy to reduce ABCB1 and increase AMPK gene levels (Table 4). The success of this study will indicate metformin as a tool to improve ALL treatment and reduce the relapse rate of ALL.

Lymphoma

Lymphoma is a malignancy resulting from an uncontrolled proliferation of lymphocytes and is classified as Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL), which represent 10% and 90% of lymphomas, respectively (161,162). Moreover, HL can be classical or nonclassical type and NHL can be divided into B-cell, T-cell, or natural killer (NK) cell types (162). In the USA (2009–2013) the incidence of lymphoma was 22/100,000 people with an average age of diagnosis of 63 years old (162). Although the improvement of survival rate is 72% at 5 years (162), cases of resistant and relapse lymphomas are increasing, thus, new therapies to overcome this scenario are essential.

mTOR pathway is currently activated in lymphomas, being important for tumorigenesis and drug resistance (163-167). Shi et al. showed a higher mTOR activation in B- and T-lymphoma cells associated with AMPK inactivation. When treated with metformin, AMPK was activated leading to the inhibition of mTOR and proliferation of both T and B lymphoma cells, similar effects were also observed in vivo (168) (Figure 5) (Table 5). In the study, metformin was also able to enhance the anti-lymphoma action of doxorubicin in vitro and in vivo (168) (Table 5).

Figure 5 Metformin as a therapy to overcome resistance in lymphomas. The mTOR pathway is frequently activated in lymphomas, contributing to drug resistance. Metformin can inhibit the mTOR pathway through AMPK activation in B and T-lymphoma cells, both in vitro and in vivo. Beyond that, a high rate of glycolysis in BL lymphoma is common and important to treatment failure. In this context, metformin can induce alterations in glucose consumption in BL cells, impacting the glycolysis rate. Purposing metformin as a tool to improve treatment success and survival. mTOR, mammalian target of rapamycin; AMPK, adenosine monophosphate-activated protein kinase; BL, Burkitt lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is responsible for 35–40% of NHL cases, and similar to DLBCL is the follicular lymphoma grade 3b (FL3b), a type of NHL with the same therapy for DLBCL (169) (Table 5). The first-line treatment involves the use of rituximab + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), despite its efficiency rate of 75–80%, nearly 30–40% of responsiveness patients relapse (172,173). To overcome the relapse of DLBCL patients, autologous stem-cell transplantation (ASCT) can be used, however, this therapy is toxic for older and weakened patients (172). Therefore, therapeutic agents that can reduce the relapse rate of DLBCL patients are interesting. Fan et al. conducted a phase 2 clinical trial where 245 CR patients with DLBCL or FL3b have treated with/out metformin + rituximab + CHOP, resulting in an enhancement of survival time in both low and high risk for relapse patients and decreased the relapse rate when compared to non-metformin group (5% vs. 9.2%) (169) (Table 5).

Singh et al. (170) performed an in vitro study with lymphoma cell lines, sensitive (RSCL) and resistant (RRCL) to rituximab. The treatment with metformin reduced cell viability, proliferation, ATP levels and induced apoptosis, loss of MMP, ROS generation, and cell cycle arrest in the G1 phase, as monotherapy both in RSCL and RRCL cells (172). Metformin also acts as an adjuvant agent, increasing doxorubicin and dexamethasone anti-lymphoma effect both in RSCL and RRCL. In vivo, metformin exerts an adjuvant effect, enhancing the anti-lymphoma activity of rituximab and the survival time of animals, which was 72.5 days with metformin and 51.5 days without metformin (170) (Table 5). Highlighting the capacity of metformin to resensitize resistant lymphoma cells to therapy, beyond its potential use as monotherapy in sensitive and resistant lymphomas.

Burkitt lymphoma (BL) is a rare and aggressive NHL. Although therapies advance, the relapse of BL can occur and new options to treat BL are necessary (174). Bagaloni et al. demonstrated that DAUDI cells (BL) have a higher rate of aerobic glycolysis, which is linked to the Warburg effect, but when metformin was applied it resulted in reduced cell viability and alterations in glucose consumption (171) (Table 5). A high rate of glycolysis is important for tumorigenesis and is associated with drug resistance and tumor recurrence (175,176). Therefore, through modifications of glucose usage, metformin can limit drug resistance and cases of relapse, constituting an alternative therapeutic tool for aggressive lymphoma (Figure 5).

Due to the good perspective of the metformin uses to avoid relapse, a phase 2 clinical trial of metformin use as maintenance therapy for DLBCL and stage 3 follicular lymphoma patients in CR with high risk of relapse is on course (NCT03600363) (Table 4).

MM

MM is a HM characterized by a clonal proliferation of plasma cells, which are mature antibody-producing B cells found in the bone marrow and important for humoral immunity, promoting monoclonal antibody production and organ injury (177). MM was responsible for 160,000 cases in 2018, corresponding to 0.9% of all cancers, and 106,000 deaths (1.1% of cancer deaths), indicating a high mortality rate (177). The median age of diagnosis is around 65–74 years old, whereas its occurrence among people under 40 years old is rare (178). The first-line therapy is autologous hematopoietic stem cell transplantation (HSCT), for patients not indicated to HSCT, triple therapy with proteasome inhibitor, immunomodulator, and steroid drugs (bortezomib, lenalidomide and, dexamethasone), known as VRd therapy is recommended (179,180). Currently, CAR-T cell therapy is approved by the FDA to use as an MM immunotherapy (178). Despite the advances in MM treatment, many MM patients relapse and tend to a refractory disease (181). Associated with the higher mortality and relapse rate, MM is considered a treatable, but incurable disease.

MM has a higher glucose uptake, which is linked to drug resistance in many tumors, such as in MM (182,183). Due to the importance of glycolysis to MM, ritonavir (GLUT4 inhibitor) is used to treat MM, however, resistant cases can occur (184-186). Dalva-Aydemir et al. evaluated the use of another metabolic disruptor, metformin together with ritonavir in MM, resulting in a synergetic cytotoxicity in vitro, beyond the reduction of tumor weight, tumor regressed and a prolonged survival in vivo by this combination. The cytotoxicity effects were associated with the impairment of energetic metabolism of MM (187) (Table 6). Thus, metformin can act as a ritonavir sensitizer in MM (Figure 6).

Figure 6 Metformin and its effects in MM to overcome resistance. Metformin is able to: (I) enhance ritonavir cytotoxicity, leading to the impairment of MM metabolism and sensitizing MM cells to ritonavir; (II) enhance fingolimod effect by the reduction of Bcl-2 proteins amount, inhibition of PI3K/Akt/mTOR pathway, loss of MMP, ER stress and ROS generation and (III) overcoming bortezomib resistance through the reduction of GRP78 levels, leading to apoptosis and decreasing autophagy of MM cells. MM, multiple myeloma; PI3K/Akt/mTOR, phosphatidylinositol-3-kinase/Akt and mammalian target of rapamycin; MMP, mitochondrial membrane potential; ER, endoplasmic reticulum; ROS, reactive oxygen species; GRP78, glucose-regulated protein 78.

Zhao et al. showed that metformin + FTY720 (fingolimod, an immunomodulator) has a stronger cytotoxicity effect in MM, promoting apoptosis through reducing anti-apoptotic Bcl-2 proteins (including Mcl-1, which is related to the worst prognosis of MM), endoplasmic reticulum (ER) stress, inhibition of PI3K/Akt/mTOR, loss of MMP and ROS generation (188) (Figure 6) (Table 6). Wang et al. presented metformin as a promising anti-MM drug in monotherapy, being able to block MM proliferation through autophagy and induced cell cycle arrest in G0/G1 phase by mTORC1/C2 inhibition and AMPK activation, in vitro. Similar effects were also observed in vivo, where metformin exerts an anti-MM effect associated with AMPK activation, reduced proliferation, and mTOR inhibition (189) (Table 6). Establishing metformin as an adjuvant agent to improve MM therapy.

Despite bortezomib efficacy, cases of resistance are a challenge. Jagannathan et al. discovered in MM patients an upregulation of the HSPA5 gene, which encodes the UPR effector glucose-regulated protein 78 (GRP78) and was related to failed response to bortezomib. The study demonstrated that metformin + bortezomib suppresses GRP78, reducing autophagy and increasing apoptosis (Figure 6). Furthermore, it exerts a higher cytotoxicity in stem cell-like side population (chemoresistant population) and in vivo (190) (Table 6).

Melphalan is an alkylating drug used in the treatment of MM, despite its efficiency, cases of resistance and relapse are common (192,193). Song et al. performed a study where metformin enhanced the anti-MM effect of melphalan, inducing higher DNA damage, apoptosis, and reducing ATP concentration (191) (Table 6). Indicating metformin as a tool to improve MM sensitivity to melphalan.

An important source of drug resistance and relapse in MM is the population of MM cancer stem cells (MM CSCs), which can survive the treatment through drug efflux and detoxifying capacity (181,194). Many studies have demonstrated the action of metformin in CSCs, possibly the inhibition of these cells and the improvement of therapy efficiency through the reduction of drug resistance and recurrence rate among cancers (195,196).

Due to the potential use of metformin in MM, some clinical trials related to its action in relapse MM are in progress. The phase 2 NCT02967276 study evaluates the effect of metformin + dexamethasone in relapsed/refractory MM. The phase 1 NCT03829020 study aims to identify the correct dose and side effects of metformin + nelfinavir + bortezomib treatment in relapsed/refractory MM. Another phase 1 study, NCT02948283, evaluates the effect of metformin + ritonavir in relapsed/refractory MM or CLL (Table 4). Demonstrating metformin as a promised therapeutic approach to relapse/refractory MM patients.

Conclusions

The growing understanding of the metformin mode of action in tumor cell metabolism is central to understanding its adjuvant potential observed in clinical trials. Among several features of growing malignancy for most tumors, is the enhancement of aerobic glycolysis, even in conditions of normoxia. However, in some HMs while some oncogenic signaling favors glycolysis, in other HMs OXPHOS is favored, enhancing sensitivity towards metformin. The metformin action on CI and in AMPK activation may induce apoptosis of T-cell acute lymphoblastic leukemia (T-ALL), while it is less toxic to CD4⁺ T-lymphocytes from healthy donors. These biochemical features elicited by metformin demonstrated the capacity of metformin to act in HMs, being able to enhance the effect and the sensitivity of anti-HMs drugs, and its action in resistant, relapse, and refractory HMs, both in vitro and in vivo studies.

Acknowledgments

Funding: The present study was supported by the Research Support Foundation of Rio de Janeiro (FAPERJ), grant No. E-26/201.591/2021.

Footnote

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-157/coif). The authors have no conflicts of interest to declare.

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