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Bisphosphonates are well established in the management of cancer-induced bone disease. Recent studies have indicated that these compounds have direct inhibitory effects on cultured human breast cancer cells. Nitrogen-containing bisphosphonates including zoledronic acid have been shown to induce apoptosis associated with PARP cleavage and DNA fragmentation. The aim of this study was to identify the signalling pathways involved. Forced expression of the anti-apoptotic protein bcl-2 attenuated bisphosphonate-induced loss of cell viability and induction of DNA fragmentation in MDA-MB-231 cells. Zoledronic acid-mediated apoptosis was associated with a time and dose-related release of mitochondrial cytochrome c into the cytosol in two cell lines. Rescue of cells by preincubation with a caspase-3 selective inhibitor and demonstration of procaspase-3 cleavage products by immunoblotting suggests that at least one of the caspases activated in response to zoledronic acid treatment is caspase-3. In both MDA-MB-231 and MCF-7 breast cancer cells, zotedronic acid impaired membrane Iocalisation of Ras indicating reduced prenylation of this proten. These observations demonstrate that zoledroric acidmediated apoptosis is associated with cytochrome c release and consequent caspase activation, This process may be initiated by inhibition of the enzymes in the mevalonate pathway leading to impaired prenylation of key intracellular proteins including Ras. [ABSTRACT FROM AUTHOR]

Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10-15 microg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82-532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states. [ABSTRACT FROM AUTHOR]

Organometallic complexes of fac-tricarbonylrhenium have been shown to exhibit anticancer properties. Anthrapyrazole anticancer agents act as DNA intercalators and topoisomerase IIα inhibitors, leading to double-strand breaks (DBS) and cell cycle arrest. This work involves the synthesis and biological evaluation of novel fac-tricarbonyl-rhenium complexes with anthrapyrazole derivatives. The anthrapyrazole moiety was synthesized from 1,8-dihydroxyanthraquinone, and three ligands L1, L2 and L3 were prepared. Ligand L1 coordinates via the phenolic O and pyrazole N as bidentate chelator forming the fac-[Re(CO)3(κ2-N,O)(MeOH)]-type complex, ReL1. Ligand L2 contains a pendant picolylamine N,N′-chelating system, forming the bidentate fac-[Re(CO)3(κ2-N,N′)Br]-type complex, ReL2. Ligand L3 contains a pendant picolylaminomonoacetic acid chelating system, forming a tridentate fac-[Re(CO)3(κ3-N,N′,O)]-type complex, ReL3. Complex ReL4 contains a picolylamine chelator, forming a complex with structure fac-[Re(CO)3(κ2-N,N′)Br], which was synthesized as a model for ReL2, and its coordination mode was resolved by X-ray crystallography. The complexes were characterized spectroscopically, and their biological properties were evaluated in vitro, in terms of DNA binding as well as for the cytotoxicity against CT-26 tumor cell line. Tumor cell cytotoxicity was high for ligand L2 and complex ReL2, exhibiting IC50 values of 0.36 and 0.64 μΜ, respectively. The most promising complex ReL2 was evaluated further by the preparation of its congener γ-emitting technetium-99m radio-complex, 99mTcL2. The in vitro uptake in CT26 tumor cells and the in vivo uptake in CT26 tumor-bearing mice of 99mTcL2 was determined, and its pharmacokinetic profile was established. These data indicate that the 99mTc complex has suitable properties to enter tumor cells in vitro and in vivo, and therefore ReL2 is promising for further evaluation. [ABSTRACT FROM AUTHOR]

Simple Summary: Vitamin D supplementation's effectiveness in reducing cancer is widely debated. The controversy may be explained by differences in 25(OH)D3 metabolism. Previous studies showed that breast cancer cells produce vitamin D3 metabolites locally, and their ability to regulate tumorigenesis is related to the presence of estrogen receptor alpha 66 (ERα66). The present study examined this process in another estrogen-dependent cancer, laryngeal cancer. This study evaluated the effects of the active vitamin D3 metabolite 24R,25(OH)2D3 on cell growth, whether these cells can produce their own secreted vitamin D3 metabolites, and whether this ability is related to the presence or absence of ERα66. To address these questions, ERα-positive (UM-SCC-12) and ERα-negative (UM-SCC-11A) laryngeal cancer cell lines were examined for the presence of ERα66; the enzymes responsible for metabolizing 25(OH)D3 (CYP24A1 and CYP27B1); the local production of 24,25(OH)2D3 and 1,25(OH)2D3; and the effect of 24R,25(OH)2D3 on cell growth and markers of metastasis. The results showed that laryngeal cancer cells express CYP24A1 and CYP27B1, produce 24,25(OH)2D3, and respond differently to 24R,25(OH)2D3, in correlation with ERα66 levels. These findings suggest that tumor cells locally produce vitamin D metabolites to regulate their growth, which must be considered when recommending vitamin D supplementation. Studies have evaluated vitamin D3's therapeutic potential in estrogen-responsive cancers, with conflicting findings. We have shown that the proliferation of breast cancer cells is regulated by 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) depending on estrogen receptor alpha 66 (ERα66) expression, suggesting that this could also be the case for estrogen-sensitive laryngeal cancer cells. Accordingly, we examined levels of ERα isoforms in ERα66-positive UM-SCC-12 and ERα66-negative UM-SCC-11A cells and their response to 24R,25(OH)2D3. 24R,25(OH)2D3 stimulated proliferation, increased the expression of metastatic markers, and inhibited apoptosis in UM-SCC-12 cells while having the opposite effect in UM-SCC-11A cells. To evaluate if vitamin metabolites could act via autocrine/paracrine mechanisms, we assessed the expression, protein levels, and activity of vitamin D3 hydroxylases CYP24A1 and CYP27B1. Both cell types expressed both mRNAs; but the levels of the enzymes and their activities were differentially regulated by estrogen. ERα66-negative UM-SCC-11A cells produced more 24,25(OH)2D3 than UM-SCC-12 cells, but comparable levels of 1,25(OH)2D3 when treated with 25(OH)D3 These results suggest that the regulation of vitamin D3 metabolism in laryngeal cancer cells is modulated by ERα66 expression, and support a role for 24R,25(OH)2D3 as an autocrine/paracrine regulator of laryngeal cancer. The local metabolism of 25(OH)D3 should be considered when determining the potential of vitamin D3 in laryngeal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Early prostate cancer treatment with radiation therapy is effective but involves substantial harmful side effects throughout therapy. This study explores the use of the metabolic modulator lonidamine (LND) to sensitize prostate cancer cells to radiation therapy. 1H and 31P magnetic resonance spectroscopy (MRS) were used to non-invasively monitor metabolic changes associated with LND treatment in human prostate cancer tumors implanted in athymic nude mice. The in vivo MRS results were substantiated using classic biochemistry methods by gathering in vitro data from isolated human prostate cancer cell lines. A radiation growth delay experiment performed in xenografted mice combining LND and radiation therapy showed that LND-modified prostate cancer metabolism and significantly increased the efficacy of radiation therapy. These findings indicate that less radiation may be required with LND, reducing side effects, and potentially improving patient management in the clinic. Prostate cancer is a multi-focal disease that can be treated using surgery, radiation, androgen deprivation, and chemotherapy, depending on its presentation. Standard dose-escalated radiation therapy (RT) in the range of 70–80 Gray (GY) is a standard treatment option for prostate cancer. It could be used at different phases of the disease (e.g., as the only primary treatment when the cancer is confined to the prostate gland, combined with other therapies, or as an adjuvant treatment after surgery). Unfortunately, RT for prostate cancer is associated with gastro-intestinal and genitourinary toxicity. We have previously reported that the metabolic modulator lonidamine (LND) produces cancer sensitization through tumor acidification and de-energization in diverse neoplasms. We hypothesized that LND could allow lower RT doses by producing the same effect in prostate cancer, thus reducing the detrimental side effects associated with RT. Using the Seahorse XFe96 and YSI 2300 Stat Plus analyzers, we corroborated the expected LND-induced intracellular acidification and de-energization of isolated human prostate cancer cells using the PC3 cell line. These results were substantiated by non-invasive 31P magnetic resonance spectroscopy (MRS), studying PC3 prostate cancer xenografts treated with LND (100 mg/kg, i.p.). In addition, we found that LND significantly increased tumor lactate levels in the xenografts using 1H MRS non-invasively. Subsequently, LND was combined with radiation therapy in a growth delay experiment, where we found that 150 µM LND followed by 4 GY RT produced a significant growth delay in PC3 prostate cancer xenografts, compared to either control, LND, or RT alone. We conclude that the metabolic modulator LND radio-sensitizes experimental prostate cancer models, allowing the use of lower radiation doses and diminishing the potential side effects of RT. These results suggest the possible clinical translation of LND as a radio-sensitizer in patients with prostate cancer. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency is currently a significant public health issue closely linked to numerous diseases, such as breast cancer. This study aims to determine the estimated optimal serum levels of vitamin D to have a protective effect against breast cancer, in addition to exploring the biological mechanisms and risk factors involved. A literature search of articles published in the last 5 years was conducted, and simple statistical analyses using mean and standard deviation were performed to calculate the average concentration of vitamin D from different available studies. It has been observed that serum levels of vitamin D ≥ 40.26 ng/mL ± 14.19 ng/mL could exert a protective effect against breast cancer. Additionally, various biological mechanisms, such as those related to the immune system, and risk factors like diet implicated in this relationship were elucidated. Consequently, it can be concluded that proper serum levels of vitamin D may have a protective effect against breast cancer, and dietary supplementation may be an appropriate procedure to achieve these optimal vitamin D concentrations. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most prevalent tumors among women. Its prognosis and treatment outcomes depend on factors related to tumor cell biology. However, recent studies have revealed the critical role of the tumor microenvironment (TME) in the development, progression, and treatment response of breast cancer. In this review, we explore the different components of the TME and their relevance as prognostic and predictive biomarkers in breast cancer. In addition, techniques for assessing the tumor microenvironment, such as immunohistochemistry or gene expression profiling, and their clinical utility in therapeutic decision-making are examined. Finally, therapeutic strategies targeting the TME are reviewed, highlighting their potential clinical benefits. Overall, this review emphasizes the importance of the TME in breast cancer and its potential as a clinical tool for better patient stratification and the design of personalized therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Glucose metabolic reprogramming is a process in which cells alter the way that glucose is utilized. In breast cancer, cells can undergo this process to fuel their growth, acquire drug resistance, and become metastatic. Scientists have been studying this process to identify new targets for breast cancer treatment. By understanding what enzymes and pathways are involved, researchers may be able to develop drugs that specifically target these pathways, ultimately leading to more effective and less toxic treatments for breast cancer in the future. The involvement of glucose metabolic reprogramming in breast cancer progression, metastasis, and therapy resistance has been increasingly appreciated. Studies in recent years have revealed molecular mechanisms by which glucose metabolic reprogramming regulates breast cancer. To date, despite a few metabolism-based drugs being tested in or en route to clinical trials, no drugs targeting glucose metabolism pathways have yet been approved to treat breast cancer. Here, we review the roles and mechanisms of action of glucose metabolic reprogramming in breast cancer progression and drug resistance. In addition, we summarize the currently available metabolic inhibitors targeting glucose metabolism and discuss the challenges and opportunities in targeting this pathway for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer cells travel via the bloodstream to the bone before the cancer is detectable in the breast. These disseminated cells are resistant to adjuvant chemotherapy and hormone therapy administered for the very purpose of eliminating them. They recur steadily for more than 20 years, resulting in incurable diseases. The bone marrow location, or niche, which normally provides a nest for blood-forming cells to enable them to generate blood for the entire lifetime of an individual, also protects these disseminated tumor cells and places them into a state of quiescence called dormancy. Dormant cancer cells can wake up from stimulation by life events, including a gradual increase in bone marrow fat cells and loss of estrogen with aging, inflammation, new blood vessel formation, trauma, surgery, abnormal blood clotting conditions, anxiety and depression. Many investigations have tested ways of killing disseminated cells or keeping them dormant, and some have entered clinical trials. Up to 40% of patients with breast cancer (BC) have metastatic cells in the bone marrow (BM) at the initial diagnosis of localized disease. Despite definitive systemic adjuvant therapy, these cells survive in the BM microenvironment, enter a dormant state and recur stochastically for more than 20 years. Once they begin to proliferate, recurrent macrometastases are not curable, and patients generally succumb to their disease. Many potential mechanisms for initiating recurrence have been proposed, but no definitive predictive data have been generated. This manuscript reviews the proposed mechanisms that maintain BC cell dormancy in the BM microenvironment and discusses the data supporting specific mechanisms for recurrence. It addresses the well-described mechanisms of secretory senescence, inflammation, aging, adipogenic BM conversion, autophagy, systemic effects of trauma and surgery, sympathetic signaling, transient angiogenic bursts, hypercoagulable states, osteoclast activation, and epigenetic modifications of dormant cells. This review addresses proposed approaches for either eliminating micrometastases or maintaining a dormant state. [ABSTRACT FROM AUTHOR]

Cancer has been progressively a major global health concern. With this developing global concern, cancer determent is one of the most significant public health challenges of this era. To date, the scientific community undoubtedly highlights mitochondrial dysfunction as a hallmark of cancer cells. Permeabilization of the mitochondrial membranes has been implicated as the most considerable footprint in apoptosis-mediated cancer cell death. Under the condition of mitochondrial calcium overload, exclusively mediated by oxidative stress, an opening of a nonspecific channel with a well-defined diameter in mitochondrial membrane allows free exchange between the mitochondrial matrix and the extra mitochondrial cytosol of solutes and proteins up to 1.5 kDa. Such a channel/nonspecific pore is recognized as the mitochondrial permeability transition pore (mPTP). mPTP has been established for regulating apoptosis-mediated cancer cell death. It has been evident that mPTP is critically linked with the glycolytic enzyme hexokinase II to defend cellular death and reduce cytochrome c release. However, elevated mitochondrial Ca2+ loading, oxidative stress, and mitochondrial depolarization are critical factors leading to mPTP opening/activation. Although the exact mechanism underlying mPTP-mediated cell death remains elusive, mPTP-mediated apoptosis machinery has been considered as an important clamp and plays a critical role in the pathogenesis of several types of cancers. In this review, we focus on structure and regulation of the mPTP complex-mediated apoptosis mechanisms and follow with a comprehensive discussion addressing the development of novel mPTP-targeting drugs/molecules in cancer treatment. [ABSTRACT FROM AUTHOR]

Intensive epigenome and transcriptome analyses have unveiled numerous biological mechanisms, including the regulation of cell differentiation, proliferation, and induced apoptosis in neoplastic cells, as well as the modulation of the antineoplastic action of the immune system, which plausibly explains the observed population-based relationship between low vitamin D status and increased cancer risk. However, large randomized clinical trials involving cholecalciferol supplementation have so far failed to show the potential of such interventions in cancer prevention. In this article, we attempt to reconcile the supposed contradiction of these findings by undertaking a thorough review of the literature, including an assessment of the limitations in the design, conduct, and analysis of the studies conducted thus far. We examine the long-standing dilemma of whether the beneficial effects of vitamin D levels increase significantly above a critical threshold or if the conjecture is valid that an increase in available cholecalciferol translates directly into an increase in calcitriol activity. In addition, we try to shed light on the high interindividual epigenetic and transcriptomic variability in response to cholecalciferol supplementation. Moreover, we critically review the standards of interpretation of the available study results and propose criteria that could allow us to reach sound conclusions in this field. Finally, we advocate for options tailored to individual vitamin D needs, combined with a comprehensive intervention that favors prevention through a healthy environment and responsible health behaviors. [ABSTRACT FROM AUTHOR]

Simple Summary: The effect of vitamin D3 on the development of breast cancer (favorable, ineffective, or even unfavorable) depends on many factors, such as age, menopausal status, or obesity. The immunomodulatory effect of vitamin D may be unfavorable in case of breast cancer progression. The effect of vitamin D on Th17 cells may depend on disease type and patients' age. Our goal was to summarize the data available and to find indications of vitamin D treatment failure or success. Therefore, in this review, we present data describing the effects of vitamin D3 on Th17 cells, mainly in breast cancer. Vitamin D3, which is well known to maintain calcium homeostasis, plays an important role in various cellular processes. It regulates the proliferation and differentiation of several normal cells, including immune and neoplastic cells, influences the cell cycle, and stimulates cell maturation and apoptosis through a mechanism dependent on the vitamin D receptor. The involvement of vitamin D3 in breast cancer development has been observed in numerous clinical studies. However, not all studies support the protective effect of vitamin D3 against the development of this condition. Furthermore, animal studies have revealed that calcitriol or its analogs may stimulate tumor growth or metastasis in some breast cancer models. It has been postulated that the effect of vitamin D3 on T helper (Th) 17 lymphocytes is one of the mechanisms promoting metastasis in these murine models. Herein we present a literature review on the existing data according to the interplay between vitamin D, Th17 cell and breast cancer. We also discuss the effects of this vitamin on Th17 lymphocytes in various disease entities known to date, due to the scarcity of scientific data on Th17 lymphocytes and breast cancer. The presented data indicate that the effect of vitamin D3 on breast cancer development depends on many factors, such as age, menopausal status, or obesity. According to that, more extensive clinical trials and studies are needed to assess the importance of vitamin D in breast cancer, especially when no correlations seem to be obvious. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the most common endocrine malignancy and exhibits rising incidence. Annual incidence varies by sex, age, and geographical location. It has been reported that impairment of vitamin D signalling promotes thyroid cancer progression. Recent studies have shown that vitamin D, a fat-soluble vitamin that acts as both a nutrient and a hormone, may have utility in the prevention of autoimmune thyroid-related diseases. However, the precise role of vitamin D in the pathobiology of thyroid cancer is controversial. Previous studies have suggested that elevated serum vitamin D levels have a protective role in thyroid cancer. However, there is also evidence demonstrating no inverse relationship between vitamin D levels and the occurrence of thyroid cancer. Furthermore, recent data provide evidence that circulating vitamin D concentration is inversely correlated with disease aggressiveness and poor prognosis, while evidence of an association with tumour initiation remains weak. Nevertheless, a variety of data support an anti-tumorigenic role of vitamin D and its potential utility as a secondary chemopreventive agent. In this review, we highlighted recent findings regarding the association of vitamin D status with the risk of thyroid cancer, prognosis, potential mechanisms, and possible utility as a chemopreventive agent. [ABSTRACT FROM AUTHOR]

Background: Vitamin D exerts multiple beneficial effects in humans, including neuronal, immune, and bone homeostasis and the regulation of cardiovascular functions. Recent studies correlate vitamin D with cancer cell growth and survival, but meta-analyses on this topic are often not consistent. Methods: A systematic search of the PubMed database and the Clinical Trial Register was performed to identify all potentially relevant English-language scientific papers containing original research articles on the effects of vitamin D on human health. Results: In this review, we analyzed the antioxidant and anti-inflammatory effects of vitamin D against acute and chronic diseases, focusing particularly on cancer, immune-related diseases, cardiomyophaties (including heart failure, cardiac arrhythmias, and atherosclerosis) and infectious diseases. Conclusions: Vitamin D significantly reduces the pro-oxidant systemic and tissue biomarkers involved in the development, progression, and recurrence of chronic cardiometabolic disease and cancer. The overall picture of this review provides the basis for new randomized controlled trials of oral vitamin D supplementation in patients with cancer and infectious, neurodegenerative, and cardiovascular diseases aimed at reducing risk factors for disease recurrence and improving quality of life. [ABSTRACT FROM AUTHOR]

An approach using multivariate adaptive regression splines (MARSplines) was applied for quantitative structure–activity relationship studies of the antitumor activity of anthrapyrazoles. At the first stage, the structures of anthrapyrazole derivatives were subjected to geometrical optimization by the AM1 method using the Polak–Ribiere algorithm. In the next step, a data set of 73 compounds was coded over 2500 calculated molecular descriptors. It was shown that fourteen independent variables appearing in the statistically significant MARS model (i.e., descriptors belonging to 3D-MoRSE, 2D autocorrelations, GETAWAY, burden eigenvalues and RDF descriptors), significantly affect the antitumor activity of anthrapyrazole compounds. The study confirmed the benefit of using a modern machine learning algorithm, since the high predictive power of the obtained model had proven to be useful for the prediction of antitumor activity against murine leukemia L1210. It could certainly be considered as a tool for predicting activity against other cancer cell lines. [ABSTRACT FROM AUTHOR]