Search Results (60)

Tamoxifen remains the standard treatment for hormone-sensitive breast cancer. However, significant interindividual variability in treatment response is observed. This variability may be partially explained by differences in the biotransformation of tamoxifen, a prodrug, into its active metabolites. To address this, we conducted a comprehensive literature search across several databases to examine current evidence on single-gene and multi-gene variations throughout the metabolic and transport pathways of tamoxifen and their impact on pharmacokinetics and clinical efficacy. We also explore the influence of drug–drug–gene interactions and review clinical strategies currently employed to manage treatment variability. Overall, growing evidence highlights the influence of pharmacogenetic variability, particularly CYP2D6 polymorphisms, on tamoxifen metabolism. Although its clinical use remains cautious and limited, a combined approach involving pharmacogenetic testing and therapeutic monitoring or phenotyping may help address treatment variability. Full article

Background/Objectives: Tamoxifen, a selective estrogen receptor modulator widely used as an adjunct in the treatment of breast cancer, has known effects on bone metabolism, although its impact on osseointegration and cellular responses during early bone healing remains unclear. Understanding these effects is essential given the increasing use of dental implants in cancer survivors. The study aimed to observe the influence of tamoxifen on human osteosarcoma (SAOS-2) cells lines, as well on the osseointegration of titanium implants in ovariectomized female rats. Methods: SAOS-2 cells were incubated with Dulbecco’s modified growth medium. Six titanium (Ti) disks were used at each time point. The samples were divided into groups with the presence (TAM, n = 36) or not (CTR, n = 36) of tamoxifen in a concentration of 2 μM. In vivo, 72 animals were divided in groups with bilateral ovariectomy or SHAM and tamoxifen administration or not (15 mg/kg). Cell viability, mineralization rate, and collagen synthesis were assessed, as well as bone/implant contact (BIC) and bone ingrowth (BIN). Results: Tamoxifen caused a decrease in SAOS-2 viability, although an increase in the mineralization rate was observed. In vivo, the TAM groups presented higher BIC and BIN when compared to their control, but a lower percentage of mature collagen cells. Conclusions: Based on our findings, in vitro, the therapy with TAM slightly reduced the viability of SAOS-2 cells while significantly increasing the mineralization rate. In vivo, the therapy positively influenced BIC and BIN during the osseointegration phase. Full article

Long-chain fatty acids (LCFAs) have emerged as important regulators of cancer metabolism, but their impact on hormone receptor expression in breast cancer (BCA) remains poorly understood. In this study, we investigated the effects of five LCFAs—linoleic acid (LA), oleic acid (OA), elaidic acid (EA), palmitic acid (PA), and α-linolenic acid (LNA)—on two BCA cell lines: luminal-type MCF7 and triple-negative MDA-MB-231 (MB231). All LCFAs suppressed cell viability and mitochondrial function in a dose-dependent manner, accompanied by decreased membrane potential, increased reactive oxygen species production, and a metabolic shift. Notably, OA reduced both mRNA and nuclear protein levels of estrogen receptor alpha (ERα) in MCF7 cells, leading to impaired responses to estradiol and tamoxifen. In contrast, PA induced nuclear ERα expression in MB231 cells, although ER signaling remained inactive. MicroRNA profiling revealed that OA upregulated ER-suppressive miR-22 and miR-221 in MCF7, while PA increased miR-34a in MB231, contributing to ERα induction. These findings suggest that specific LCFAs modulate ER expression through epigenetic and post-transcriptional mechanisms, altering hormonal responsiveness in BCA. Our results offer new insights into how dietary lipids may influence therapeutic efficacy and tumor behavior by regulating nuclear receptor signaling. Full article

The metabolism of drugs and foreign substances in humans typically involves multiple enzymatic steps, particularly in phase-1 biotransformation in the liver, where various cytochrome P450 monooxygenases (CYPs) play crucial roles. This complexity can lead to a wide range of metabolites. Understanding the contributions of individual CYPs and their interactions within these intricate enzyme cascades can be challenging. We recently developed an in vitro biotransformation platform employing various Chinese Hamster Ovarian (CHO) cell clones. These clones express human cytochrome P450 oxidoreductase (CPR), and each is defined by a specific human CYP enzyme expression, thus exhibiting no detectable endogenous CYP enzyme activity (mono-CYP CHO platform). In this study, we investigated whether the mono-CYP CHO platform is a suitable tool for modeling complex drug metabolization reactions in vitro. Tamoxifen (TAM) was selected as a model substance due to its role as a prodrug widely used in breast cancer therapy, where its main active metabolite, endoxifen, arises from a two-step metabolism primarily involving the CYP system. Specifically, the combined activity of CYP3A4 and CYP2D6 is believed to be essential for efficient endoxifen production. However, the physiological metabolization pathway of TAM is more complex and interconnected, and the reasons for TAM’s therapeutic success and variability among patients are not yet fully understood. Analogous to our recently introduced mono-CYP3A4 CHO cells, we generated a CHO cell line expressing human CPR and CYP2D6, including analysis of CYP2D6 expression and specific activity. Comparative studies on the metabolization of TAM were performed with both mono-CYP CHO models individually and in co-culture with intact cells as well as with isolated microsomes. Supernatants were analyzed by HPLC to calculate individual CYP activity for each metabolite. All the picked mono-CYP2D6 clones expressed similar CYP2D6 protein amounts but showed different enzyme activities. Mono-CYP2D6 clone 18 was selected as the most suitable for TAM metabolization based on microsomal activity assays. TAM conversion with mono-CYP2D6 and -3A4 clones, as well as the combination of both, resulted in the formation of the expected main metabolites. Mono-CYP2D6 cells and microsomes produced the highest detected amounts of 4-hydroxytamoxifen and endoxifen, along with N-desmethyltamoxifen and small amounts of N,N-didesmethyltamoxifen. N-desmethyltamoxifen was the only TAM metabolite detected in notable quantities in mono-CYP3A4, while 4-hydroxytamoxifen and endoxifen were present only in trace amounts. In CYP2D6/3A4 co-culture and equal mixtures of both CYP microsomes, all metabolites were detected at concentrations around 50% of those in individual clones, indicating no significant synergistic effects. In conclusion, our mono-CYP CHO model confirmed the essential role of CYP2D6 in synthesizing the active TAM metabolite endoxifen and indicated that CYP2D6 is also involved in producing the by-metabolite N,N-didesmethyltamoxifen. The differences in metabolite spectra between the two mono-CYP models highlight the CYP specificity and sensitivity of our in vitro system. Full article

Pharmacogenomics, the study of how genetic variations influence drug response, has become integral to cancer treatment as personalized medicine evolves. This review aims to explore key pharmacogenomic biomarkers relevant to cancer therapy and their clinical implications, providing an updated and comprehensive perspective on how genetic variations impact drug metabolism, efficacy, and toxicity in oncology. Genetic heterogeneity among oncology patients significantly impacts drug efficacy and toxicity, emphasizing the importance of incorporating pharmacogenomic testing into clinical practice. Genes such as CYP2D6, DPYD, UGT1A1, TPMT, EGFR, KRAS, and BRCA1/2 play pivotal roles in influencing the metabolism, efficacy, and adverse effects of various chemotherapeutic agents, targeted therapies, and immunotherapies. For example, CYP2D6 polymorphisms affect tamoxifen metabolism in breast cancer, while DPYD variants can result in severe toxicities in patients receiving fluoropyrimidines. Mutations in EGFR and KRAS have significant implications for the use of targeted therapies in lung and colorectal cancers, respectively. Additionally, BRCA1/2 mutations predict the efficacy of PARP inhibitors in breast and ovarian cancer. Ongoing research in polygenic risk scores, liquid biopsies, gene–drug interaction networks, and immunogenomics promises to further refine pharmacogenomic applications, improving patient outcomes and reducing treatment-related adverse events. This review also discusses the challenges and future directions in pharmacogenomics, including the integration of computational models and CRISPR-based gene editing to better understand gene–drug interactions and resistance mechanisms. The clinical implementation of pharmacogenomics has the potential to optimize cancer treatment by tailoring therapies to an individual’s genetic profile, ultimately enhancing therapeutic efficacy and minimizing toxicity. Full article

Capsaicin (CAP), the pain-inducing compound in chili peppers, exerts its effects mainly through the transient receptor potential vanilloid channel 1 (TRPV1), which mediates pain perception and some metabolic functions. CAP has also been demonstrated to improve performance in power sports (but not endurance sports) and does so mainly for females. CAP may also have anti-cancer effects. Many mechanisms have been explored to explain these phenomena, particularly the effects of TRPV1 activation for calcium influx, glucose transporter (GLUT) upregulation and inhibition of insulin (INS) production, but two important ones seem to have been missed. We demonstrate here that CAP binds to both INS and to the estrogen receptor (ESR1), enhancing estradiol binding. Other TRPV1 agonists, such as vanillin, vanillic acid and acetaminophen, have either no effect or inhibit estrogen binding. Notably, TRPV1, ESR1 and INS share significant regions of homology that may aid in identifying the CAP-binding site on the ESR1. Because activation of the estrogen receptor upregulates GLUT expression and thereby glucose transport, we propose that the observed enhancement of performance in power sports, particularly among women, may result, in part, from CAP enhancement of ESR1 function and prevent INS degradation. Chronic exposure to CAP, however, may result in downregulation and internalization of ESR1, as well as TRPV1 stimulation of glucagon-like peptide 1 (GLP-1) expression, both of which downregulate GLUT expression, thereby starving cancer cells of glucose. The binding of capsaicin to the ESR1 may also enhance ESR1 antagonists such as tamoxifen, benefiting some cancer patients. Full article

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor, and distinguishing its subtypes holds significant value for diagnosis, treatment, and the prognosis. Methods: Unsupervised clustering analysis was conducted to classify HCC subtypes. Subtype signature genes were identified using LASSO, SVM, and logistic regression. Survival-related genes were identified using Cox regression, and their expression and function were validated via qPCR and gene interference. GO, KEGG, GSVA, and GSEA were used to determine enriched signaling pathways. ESTIMATE and CIBERSORT were used to calculate the stromal score, tumor purity, and immune cell infiltration. TIDE was employed to predict the patient response to immunotherapy. Finally, drug sensitivity was analyzed using the oncoPredict algorithm. Results: Two HCC subtypes with different gene expression profiles were identified, where subtype S1 exhibited a significantly shorter survival time. A subtype scoring formula and a nomogram were constructed, both of which showed an excellent predictive performance. COL11A1 and ACTL8 were identified as survival-related genes among the signature genes, and the downregulation of COL11A1 could suppress the invasion and migration of HepG2 cells. Subtype S1 was characterized by the upregulation of pathways related to collagen and the extracellular matrix, as well as downregulation associated with the xenobiotic metabolic process and fatty acid degradation. Subtype S1 showed higher stromal scores, immune scores, and ESTIMATE scores and infiltration of macrophages M0 and plasma cells, as well as lower tumor purity and infiltration of NK cells (resting/activated) and resting mast cells. Subtype S2 was more likely to benefit from immunotherapy. Subtype S1 appeared to be more sensitive to BMS-754807, JQ1, and Axitinib, while subtype S2 was more sensitive to SB505124, Pevonedistat, and Tamoxifen. Conclusions: HCC patients can be classified into two subtypes based on their gene expression profiles, which exhibit distinctions in terms of signaling pathways, the immune microenvironment, and drug sensitivity. Full article

Breast cancer treatment has advanced significantly, particularly for estrogen receptor-positive (ER+) tumors. Tamoxifen, an estrogen antagonist, is widely used; however, approximately 40% of patients develop resistance. Recent studies indicate that microRNAs, especially miR-155, play a critical role in this resistance. Our analysis of MCF-7 tamoxifen-sensitive (TAM-S) and tamoxifen-resistant (TAM-R) cells revealed that miR-155 is significantly upregulated in TAM-R cells. Overexpression of miR-155 in TAM-S cells increased resistance to tamoxifen. Additionally, genistein, a natural isoflavone from soybeans, effectively downregulated miR-155 and its targets associated with apoptosis and glucose metabolism, including STAT3 and hexokinase 2 (HK2). Notably, genistein also significantly decreased cell migration, suggesting potential anti-metastatic effects. Furthermore, genistein reduced glucose consumption, indicating its potential to overcome miR-155-mediated tamoxifen resistance and modulate the Warburg effect. These findings highlight genistein as a promising therapeutic agent for overcoming tamoxifen resistance in ER+ breast cancer and merit further investigation. Full article

Background: Estrogen receptor-positive breast cancer accounts for around 70% of all cases. Tamoxifen, an anti-estrogenic inhibitor, is the primary drug used for this type of breast cancer treatment. However, tamoxifen resistance is a major challenge in clinics. Metabolic reprogramming, an emerging hallmark of cancer, plays a key role in cancer initiation, progression, and therapy resistance. The metabolism of non-essential amino acids such as serine, proline, and glutamine is involved in tumor metabolism reprogramming. Although the association of glutamine metabolism with tamoxifen resistance has been well established, the role of proline metabolism and its critical enzyme PRODH is unknown. Objective: The aim of this study is to explore the role and mechanism of PRODH in tamoxifen resistance in breast cancer cells. Methods: PRODH and GPX4 expressions in tamoxifen-resistant cells were detected using real-time PCR and Western blot analysis. The breast cells’ response to tamoxifen was measured using MTT assays. Trans-well assays were used to detect cell migration and invasion. A Xenograft tumor assay was used to detect the role of PRODH in tumor growth. Reactive oxygen species were measured using flow cytometry. Results: PRODH expression is reduced in tamoxifen-resistant cells, and its overexpression enhances tamoxifen response in vitro and in vivo. Conversely, PRODH knockdown confers tamoxifen resistance in tamoxifen-sensitive cells. Mechanistic studies show that ferroptosis is inhibited in tamoxifen-resistant cells and overexpression of PRODH restores the ferroptosis in tamoxifen-resistant cells. Moreover, Ferrostatin-1 (Fer-1), the ferroptosis inhibitor, reversed the effect of PRODH on tamoxifen resistance. Conclusions: These findings suggest that PRODH regulates tamoxifen resistance by regulating ferroptosis in tamoxifen-resistant cells. Full article

AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment. The inhibitors were evaluated in breast cancer for both cytotoxicity and metabolic stability assays across both murine and human breast cancer cell lines. Both AQP inhibitors also affected the expression of other AQP transcripts and proteins, which demonstrates compensatory regulation between AQP family members. As a single agent, Auphen treatment in vivo extended overall survival but did not impact primary or metastatic tumor burden. However, Auphen treatment made cells more responsive to chemotherapy (doxorubicin) or endocrine treatment (tamoxifen, fulvestrant). In fact, treatment with Tamoxifen reduced overall AQP7 protein expression. RNA-seq of breast cancer cells treated with Auphen identified mitochondrial metabolism genes as impacted by Auphen and may contribute to reducing mammary tumor progression, lung metastasis, and increased therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we found that Auphen and tamoxifen cooperate to reduce breast cancer cell viability, which suggests that Auphen treatment makes the cells more susceptible to Tamoxifen. Together, this study highlights AQPs as therapeutic vulnerabilities of breast cancer metastasis that are promising and should be exploited. However, the pharmacologic results suggest additional chemical refinements and optimization of AQP inhibition are needed to make these AQP inhibitors appropriate to use for therapeutic benefit in overcoming endocrine therapy resistance. Full article

Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated steatotic liver disease (MASLD), which specifically refers to the accumulation of fat in the liver unrelated to alcohol intake. A bi-directional relationship between DILI and MASLD is likely to exist: while certain drugs can cause MASLD by acting as pro-steatogenic factors, MASLD may make hepatocytes more vulnerable to drugs. Having a pre-existing MASLD significantly heightens the likelihood of experiencing DILI from certain medications. Thus, the prevalence of steatosis within DILI may be biased by pre-existing MASLD, and it can be concluded that the genuine true incidence of DIFLD in the general population remains unknown. In certain individuals, drug-induced steatosis is often accompanied by concomitant injury mechanisms such as oxidative stress, cell death, and inflammation, which leads to the development of drug-induced steatohepatitis (DISH). DISH is much more severe from the clinical point of view, has worse prognosis and outcome, and resembles MASH (metabolic-associated steatohepatitis), as it is associated with inflammation and sometimes with fibrosis. A literature review of clinical case reports allowed us to examine and evaluate the clinical features of DIFLD and their association with specific drugs, enabling us to propose a classification of DIFLD drugs based on clinical outcomes and pathological severity: Group 1, drugs with low intrinsic toxicity (e.g., ibuprofen, naproxen, acetaminophen, irinotecan, methotrexate, and tamoxifen), but expected to promote/aggravate steatosis in patients with pre-existing MASLD; Group 2, drugs associated with steatosis and only occasionally with steatohepatitis (e.g., amiodarone, valproic acid, and tetracycline); and Group 3, drugs with a great tendency to transit to steatohepatitis and further to fibrosis. Different mechanisms may be in play when identifying drug mode of action: (1) inhibition of mitochondrial fatty acid β-oxidation; (2) inhibition of fatty acid transport across mitochondrial membranes; (3) increased de novo lipid synthesis; (4) reduction in lipid export by the inhibition of microsomal triglyceride transfer protein; (5) induction of mitochondrial permeability transition pore opening; (6) dissipation of the mitochondrial transmembrane potential; (7) impairment of the mitochondrial respiratory chain/oxidative phosphorylation; (8) mitochondrial DNA damage, degradation and depletion; and (9) nuclear receptors (NRs)/transcriptomic alterations. Currently, the majority of, if not all, adverse outcome pathways (AOPs) for steatosis in AOP-Wiki highlight the interaction with NRs or transcription factors as the key molecular initiating event (MIE). This perspective suggests that chemical-induced steatosis typically results from the interplay between a chemical and a NR or transcription factors, implying that this interaction represents the primary and pivotal MIE. However, upon conducting this exhaustive literature review, it became evident that the current AOPs tend to overly emphasize this interaction as the sole MIE. Some studies indeed support the involvement of NRs in steatosis, but others demonstrate that such NR interactions alone do not necessarily lead to steatosis. This view, ignoring other mitochondrial-related injury mechanisms, falls short in encapsulating the intricate biological mechanisms involved in chemically induced liver steatosis, necessitating their consideration as part of the AOP’s map road as well. Full article

Breast cancer (BC) has become the fifth most prevalent cause of cancer-related morbidity, attracting significant attention from researchers due to its heightened malignancy and drug resistance. Conventional chemotherapy approaches have proven inadequate in addressing all BC subtypes, highlighting the urgent need for novel therapeutic approaches or drugs. Curcumin (CUR), a phytochemical derived from Curcuma longa (turmeric), has shown substantial potential in inhibiting BC cell migration, metastasis, and proliferation. However, the use of CUR in this context comes with challenges due to its dynamic and easily degradable nature, poor aqueous solubility, low bioavailability, rapid metabolism, and swift systemic elimination, collectively limiting its clinical applications. As such, we provide an overview of the properties, synthesis, and characterization of the hybridization of CUR and its analogue with chemo-drug building blocks. We reviewed research from the last five years on CUR’s biogenesis with respect to the regulation of BC, revealing that CUR participates in arresting BC cells in the cell cycle and significantly induces apoptosis in BC cells. Information on the chemotherapeutic and antitumor mechanisms of CUR in BC, including regulation of the cell cycle, increased cell apoptosis, and inhibition of multidrug resistance (MDR), was compiled. Additionally, we provide an overview of CUR loaded into nanomaterials that are cotreated with other chemotherapeutic drugs, such as paclitaxel, thymoquinone, and tamoxifen. In this review, we discuss different types of nanoparticles that can be used for CUR delivery, such as polymeric nanoparticles, carbon nanotubes, and liposomes. By comparing the size, entrapment efficiency, drug-loading capacity, release time, biocompatibility, pharmaceutical scale, and reproducibility of various nanomaterials, we aimed to determine which formulations are better suited for loading CUR or its analogue. Ultimately, this review is expected to offer inspiring ideas, promising strategies, and potential pathways for developing advanced anti-BC strategy nanosystems in clinical practice. Full article

Tamoxifen-resistant breast cancer cells (TamR-BCCs) are characterized by an enhanced metabolic phenotype compared to tamoxifen-sensitive cells. FoxO3a is an important modulator of cell metabolism, and its deregulation has been involved in the acquisition of tamoxifen resistance. Therefore, tetracycline-inducible FoxO3a was overexpressed in TamR-BCCs (TamR/TetOn-AAA), which, together with their control cell line (TamR/TetOn-V), were subjected to seahorse metabolic assays and proteomic analysis. FoxO3a was able to counteract the increased oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) observed in TamR by reducing their energetic activity and glycolytic rate. FoxO3a caused glucose accumulation, very likely by reducing LDH activity and mitigated TamR biosynthetic needs by reducing G6PDH activity and hindering NADPH production via the pentose phosphate pathway (PPP). Proteomic analysis revealed a FoxO3a-dependent marked decrease in the expression of LDH as well as of several enzymes involved in carbohydrate metabolism (e.g., Aldolase A, LDHA and phosphofructokinase) and the analysis of cBioPortal datasets of BC patients evidenced a significant inverse correlation of these proteins and FoxO3a. Interestingly, FoxO3a also increased mitochondrial biogenesis despite reducing mitochondrial functionality by triggering ROS production. Based on these findings, FoxO3a inducing/activating drugs could represent promising tools to be exploited in the management of patients who are refractory to antiestrogen therapy. Full article

Tamoxifen (TAM) is a drug commonly used in patients with breast cancer. The anticancer effect of TAM occurs via its ability to antagonize estrogen-dependent growth of mammary epithelial cells. Previously, we demonstrated that TAM prevented the chemotherapy-induced loss of ovarian follicular reserves in both cancer-free rats and rats with cancer. Such follicular loss is a main cause of infertility in young women treated for cancer. The current study was undertaken to discover the molecules and intracellular pathways involved in the action of TAM in the ovaries of rats with mammary tumors. To meet this goal we used transcriptomic (RNA-Seq) and proteomic (2D-DIGE/MS) approaches. TAM inhibited the expression of genes and lncRNAs involved in ovarian steroidogenesis. Moreover, TAM altered the expression of genes related to primordial follicle activation or arrest. In addition, proteomic screening indicated the importance of basic metabolic processes in the ovarian actions of TAM. Although simple extrapolation of these data to humans is not possible, the results of this study emphasize the need to explore the ability of TAM to affect ovarian function in women undergoing cancer treatment. Full article

The Insulin-like Growth Factor (IGF) system in breast cancer progression has been a matter of interest for decades, but targeting this system did not result in a successful clinical strategy. The system’s complexity and homology of its two receptors—insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF-1R)—are possible causes. The IGF system maintains cell proliferation and also regulates metabolism, making it a pathway to explore. To understand the metabolic phenotype of breast cancer cells, we quantified their real-time ATP production rate upon acute stimulation with ligands—insulin-like growth factor 1 (1GF-1) and insulin. MCF-7L cells express both IGF-1R and IR, while tamoxifen-resistant MCF-7L (MCF-7L TamR) cells have downregulated IGF-1R with unchanged IR levels. Treating MCF-7L cells with 5 nM IGF-1 increased the glycolytic ATP production rate, while 10 nM insulin did not affect metabolism when compared with the control. Neither treatment altered ATP production in MCF-7L TamR cells. This study provides evidence of the relationship between metabolic dysfunction, cancer, and the IGF axis. In these cells, IGF-1R, and not IR, regulates ATP production. Full article