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Sildenafil enhances antitumor CTL activity in vivo. (A) BALB/c mice were either challenged with CT26WT cells, vaccinated with 10⁶ γ-irradiated CT26WT cells, or injected with PBS on day 0. Sildenafil was added to the drinking water where indicated. On day 12, all groups received 10⁷ AH-1–pulsed CFSEhigh-labeled BALB/c splenocytes admixed with 10⁷ HA-pulsed CFSElow-labeled BALB/c splenocytes. The mice were killed 40 h later. Single cell suspensions from spleens and tumor draining lymph nodes were analyzed by FACS. (B) BALB/c mice were either challenged with C26GM cells, vaccinated with 10⁶ γ-irradiated C26GM cells, or injected with PBS on day 0. Sildenafil was added to the drinking water on day 0. After 5 d, the mice received CFSE-labeled target splenocytes as described in A. Analysis was performed as described in the Materials and methods.
Source publication
Phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) are agents currently in clinical use for nonmalignant conditions. We report the use of PDE5 inhibitors as modulators of the antitumor immune response. In several mouse tumor models, PDE5 inhibition reverses tumor-induced immunosuppressive mechanisms and enables a measurab...
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There are no randomised and properly blinded trials directly comparing one PDE-5 inhibitor with another in a normal home setting. Valid indirect comparisons with a common comparator must examine equivalent doses, similar duration, similar populations, with the same outcomes reported in the same way.
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Differences in clinical pharmacology of the currently marketed phosphodiesterase (PDE)5 inhibitors sildenafil, vardenafil and tadalafil are largely determined by their pharmacokinetic (PK) properties and their PDE5 inhibitory activity profile. This review outlines the basic concepts of pharmacokinetics and pharmacokinetic pharmacodynamic (PK/PD) re...
Myeloid-derived suppressor cells (MDSC) producing arginase I are increased in the peripheral blood of patients with renal cell carcinoma (RCC). MDSC inhibit T-cell function by reducing the availability of L-arginine and are therefore considered an important tumor escape mechanism. We aimed to determine the origin of arginase I-producing MDSC in RCC...
Myeloid derived suppressor cells (MDSC) play a pivotal role in tumor immune evasion and MDSC levels increased in patients with cancer. Studies confirmed the associations between MDSC and various cytokines in the peripheral blood. However, little is known about the association between parenchymal MDSC subsets and cytokines, or the mechanism drawing...
We investigated the potency and the selectivity profile of vardenafil on phosphodiesterase (PDEs) enzymes, its ability to modify cGMP metabolism and cause relaxation of penile smooth muscle and its effect on erections in vivo under conditions of exogenous nitric oxide (NO) stimulation. PDE isozymes were extracted and purified from human platelets (...
Citations
... Phosphodiesterase-5 (PDE-5) inhibitors can suppress the function of MDSCs by reducing the levels of iNOS and arginase. In mouse models, PDE-5 inhibitors (e.g., sildenafil and tadalafil) activate antitumor immunity and prolong the survival of tumor-bearing mice [206,207]. In mouses model of hepatocellular carcinoma, systemic treatment with PDE-5 inhibitors may also prevent the accumulation of MDSCs in the TME induced by cytokine-induced killer (CIK) cell-derived immunotherapy in HCC through ARG1 and iNOS blockade, increasing the antitumor function of CIK cell therapy [208]. ...
Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs.
... Zoledronic acid, for example, alters the migration of these cells, and Vitamin A and Vitamin D influence their maturation and development process. Sildenafil alters their immunosuppressive function and celecoxib inhibits its expansion and immunosuppressive function [64][65][66] . Celecoxib is a COX-2-specific and commonly used non-steroidal anti-inflammatory drug. ...
... Another method of targeting MDSCs is to block the signaling pathways necessary for upregulation of effectors of immunosuppression such as Arginase I and iNOS. Previously, it had been shown that inhibition of PDE5 in purified MDSCs leads to downregulation of IL4Ra, a signaling receptor that drives increase in expression of immunosuppressive Arginase I through STAT6 signaling [89]. PDE5 inhibitors sildenafil and tadalafil have already been FDA-approved for other indications such as erectile dysfunction and pulmonary hypertension, and research has turned towards utilizing these medications in immunotherapy in cancer. ...
Gastrointestinal cancers represent one of the more challenging cancers to treat. Current strategies to cure and control gastrointestinal (GI) cancers like surgery, radiation, chemotherapy, and immunotherapy have met with limited success, and research has turned towards further characterizing the tumor microenvironment to develop novel therapeutics. Myeloid-derived suppressor cells (MDSCs) have emerged as crucial drivers of pathogenesis and progression within the tumor microenvironment in GI malignancies. Many MDSCs clinical targets have been defined in preclinical models, that potentially play an integral role in blocking recruitment and expansion, promoting MDSC differentiation into mature myeloid cells, depleting existing MDSCs, altering MDSC metabolic pathways, and directly inhibiting MDSC function. This review article analyzes the role of MDSCs in GI cancers as viable therapeutic targets for gastrointestinal malignancies and reviews the existing clinical trial landscape of recently completed and ongoing clinical studies testing novel therapeutics in GI cancers.
... Arg1 function can be directly inhibited by Arg1 inhibitors. Treatment with the Arg1 inhibitor nor-NOHA abrogated MDSC-mediated T cell suppression experimentally [34,36], and restored the proliferation of MDSC-suppressed lymphocytes from patients with multiple myeloma or head and neck squamous cell carcinoma (HNSCC) [37]. Inhibition of Arg1 via CB-1158 prevented MDSC-mediated suppression of T cell proliferation in vitro, and reduced tumour growth in multiple murine models of cancer via potentiating the effects of the chemotherapy gemcitabine and immunotherapies including immune checkpoint inhibitors, adoptive T cell or NK cell transfer [38]. ...
Cancer is the leading cause of death globally superseded only by cardiovascular diseases, and novel strategies to overcome therapeutic resistance against existing cancer treatments are urgently required. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with potent immunosuppressive capacity against well-established anti-tumour effectors such as natural killer cells (NK cells) and T cells thereby promoting cancer initiation and progression. Critically, MDSCs are readily identified in almost all tumour types and human cancer patients, and numerous studies in the past decade have recognised their role in contributing to therapeutic resistance against all four pillars of modern cancer treatment, namely surgery, chemotherapy, radiotherapy and immunotherapy. MDSCs suppress anti-tumour immunity through a plethora of mechanisms including the well-characterised arginase 1 (Arg1), inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS)-mediated pathways, along with several other more recently discovered. MDSCs are largely absent in healthy homeostatic states and predominantly exist in pathological conditions, making them attractive therapeutic targets. However, the lack of specific markers identified for MDSCs to date greatly hindered therapeutic development, and currently there are no clinically approved drugs that specifically target MDSCs. Methods to deplete MDSCs clinically and inhibit their immunosuppressive function will be crucial in advancing cancer treatment and to overcome treatment resistance. This review provides a detailed overview of the current understandings behind the mechanisms of MDSC-mediated suppression of anti-tumour immunity, and discusses potential strategies to target MDSC immunosuppressive mechanisms to overcome therapeutic resistance.
... Several studies have shown that MDSCs immunosuppression depends on Arg1, inducible nitric oxide synthase (iNOS), PD-L1, COX2, or exosomes. Thus, blocking the signaling pathways that regulate the production of suppressive factors has been developed to suppress MDSCs immunosuppression, such as COX2 inhibitor, 40 sildenafil to suppress iNOS, 41 and nitroaspirin to inhibit Arg1 and iNOS. 42 (4) Direct elimination. ...
Background
Extensive attention has been given to the role of myeloid-derived suppressor cells (MDSCs) in driving tumor progression and treatment failure. Preclinical studies have identified multiple agents that eliminate MDSCs. However, none have been authorized in the cliniccal ues due to the safety reasons. In the present study, we investigated the efficacy and mechanism of sulforaphane (SFN) to eliminate MDSCs in the tumor microenvironment (TME).
Methods
We monitored SFN effect on tumor growth and the percents or apoptosis of immune cell subsets in mice models bearing LLC or B16 cells. Flow cytometry, quantitative reverse transcription-PCR, immunohistochemistry, ELISA, immunofluorescence, imaging flow cytometry and western blot were performed to validate the role of SFN on MDSCs function in vivo and in vitro. RNA sequencing was then used to interrogate the mechanisms of how SFN regulated MDSCs function. Tumor xenograft models were established to evaluate the involvement of IL-12RB2/MMP3/FasL induced MDSCs apoptosis in vivo. We verified the effect of SFN on MDSCs and CD8 ⁺ T cells in the blood samples from a phase I clinical trial (KY-2021–0350).
Results
In this study, we elucidated that SFN liberated CD8 ⁺ T-cell antitumor ability by reducing MDSCs abundance, leading to repressed tumor growth. SFN treatment suppressed MDSCs accumulation in the peripheral blood and tumor sites of mice, but had no effect on the bone marrow. Mechanistically, SFN activates IL-12RB2, which stimulates the MMP3/FasL signaling cascade to trigger caspase 3 cleavage and induce apoptosis in MDSCs. Clinically, SFN treatment eliminates peripheral MDSCs and increases the percentage and activation of CD8 ⁺ T cells.
Conclusions
Collectively, we uncovered the role of SFN in eliminating MDSCs to emancipate CD8 ⁺ T cells through IL-12RB2/MMP3/FasL induced apoptosis, thus providing a strategy for targeting MDSCs to control tumors and improve clinical efficacy.
... Mediating caspase dependent apoptosis, and therefore cell growth arrest are the possible mechanisms for the anticancer effect via PDE5 inhibition, which could be linked to the concomitant increase in modulation of downstream pathways through the increased cGMP-PKG levels [104]. Interestingly, PDE5 inhibitors alter the tumor microenvironment by augmenting endogenous antitumor immunity via reduction of myeloid derived suppressor cell function [105]. ...
... Finally, blocking iNOS-mediated immunosuppression has also shown effects in promoting an antitumor response. For example, phosphodiesterase-5 (PDE5) inhibitors, such as sildenafil, which interfere in cGMP-dependent iNOS signaling, have been shown to prevent MDSC-mediated immunosuppression (145)(146)(147). PDE5 inhibition can reduce iNOS and Arg1 activity in MDSCs, thereby triggering antitumor response and T cell infiltration in preclinical models of colon cancer and breast cancer (145) or in patients with end-stage multiple myeloma (146). ...
... For example, phosphodiesterase-5 (PDE5) inhibitors, such as sildenafil, which interfere in cGMP-dependent iNOS signaling, have been shown to prevent MDSC-mediated immunosuppression (145)(146)(147). PDE5 inhibition can reduce iNOS and Arg1 activity in MDSCs, thereby triggering antitumor response and T cell infiltration in preclinical models of colon cancer and breast cancer (145) or in patients with end-stage multiple myeloma (146). PDE5 inhibition also prevents MDSC-induced NK suppression, increasing NK cytotoxicity in murine models and in humans with abdominal malignancy (147). ...
Immunometabolism is a burgeoning field of research that investigates how immune cells harness nutrients to drive their growth and functions. Myeloid cells play a pivotal role in tumor biology, yet their metabolic influence on tumor growth and antitumor immune responses remains inadequately understood. This Review explores the metabolic landscape of tumor-associated macrophages, including the immunoregulatory roles of glucose, fatty acids, glutamine, and arginine, alongside the tools used to perturb their metabolism to promote antitumor immunity. The confounding role of metabolic inhibitors on our interpretation of myeloid metabolic phenotypes will also be discussed. A binary metabolic schema is currently used to describe macrophage immunological phenotypes, characterizing inflammatory M1 phenotypes, as supported by glycolysis, and immunosuppressive M2 phenotypes, as supported by oxidative phosphorylation. However, this classification likely underestimates the variety of states in vivo. Understanding these nuances will be critical when developing interventional metabolic strategies. Future research should focus on refining drug specificity and targeted delivery methods to maximize therapeutic efficacy.
... This process generates nitrite and initiates the apoptosis of CD8 + T cells. PDE5 inhibitors increase the levels of cyclic guanosine monophosphate, which reduces the concentration of cell membrane Ca 2+ concentration, leading to a decrease in calcium-dependent protein kinase C activity, which prevents upregulation of IL4Rα, which in turn impairs the IL4Rα-ARG1 pathway and allows immunosuppression to be alleviated [56]. Tumor-bearing mice with functionally suppressed MDSCs exhibit increased CD8 + T cell responsiveness, suggesting that these cells play an important role in tumor-induced immunosuppression [57]. ...
Cancer is the second leading cause of death worldwide. Although multiple new cancer treatments have emerged in recent years, drug therapy, mainly comprising chemotherapy, targeted therapy, and immunotherapy, remains the most common approach. The multidrug resistance (MDR) of cancer cells to various treatments remains a challenge. Scientists have always focused on the acquired drug resistance mechanisms of tumor cells themselves. However, recent evidence shows that the tumor microenvironment (TME) plays a critical role in regulating tumor cell progression, metastasis, immune escape, and drug resistance. In the TME, interactions between cancer cells and non-malignant cells often modify the TME and facilitate drug resistance. Therefore, elucidating this complex interaction mechanism is essential for the development of effective treatments. This review focuses on the role of the TME in promoting chemoresistance in tumor cells through the following mechanisms: (i) inhibiting the immune clearance of tumor cells and facilitating immune escape responses; (ii) stimulating the release of soluble paracrine factors to enhance tumor survival and growth; (iii) promoting survival and altering drug delivery through metabolic reprogramming; (iv) obstructing drug absorption by inducing changes in stomatal cells and blood vessels surrounding the tumor; and (v) inducing the cancer stem cell phenotype. This review also addresses a clinical treatment strategy for targeting the TME, providing insights and a basis for reversing multidrug resistance.
... Recent epidemiological studies showing that PDE5 inhibitors can reduce the risk of developing CRC provides further evidence that PDE5 is an essential target for CRC chemoprevention [70]. Another consideration is the potential involvement of PDE5 in suppressing tumor immunity, as demonstrated by publications reporting that tadalafil, a PDE5 inhibitor, can activate mechanisms of antitumor immunity [64,[71][72][73]. Thus, PDE5 may be a promising molecular target for the chemoprevention of CRC, but further investigation is needed to understand better if the mechanism involves a direct effect on neoplastic cells or an indirect effect involving the activation of antitumor immunity. ...
p class="MsoNormal" style="margin-top: 6pt; line-height: 13pt; text-align: justify;"> Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/β-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future. </p
... Recent epidemiological studies showing that PDE5 inhibitors can reduce the risk of developing CRC provides further evidence that PDE5 is an essential target for CRC chemoprevention [70]. Another consideration is the potential involvement of PDE5 in suppressing tumor immunity, as demonstrated by publications reporting that tadalafil, a PDE5 inhibitor, can activate mechanisms of antitumor immunity [64,[71][72][73]. Thus, PDE5 may be a promising molecular target for the chemoprevention of CRC, but further investigation is needed to understand better if the mechanism involves a direct effect on neoplastic cells or an indirect effect involving the activation of antitumor immunity. ...
p class="MsoNormal" style="margin-top: 6pt; line-height: 13pt; text-align: justify;"> Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/β-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future. </p
