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Crocin, metformin, and their combination modulate 4T1 cell viability. Crocin (a–c) and metformin (d–f) significantly reduced cell viability in breast cancer cells (p < 0.001, compared to non-treated cells). The 4T1 cells cultured with and without crocin (0–4.5 mM) and metformin (0–20 mM) at different times (24–72 h) and cell viability were determined using MTT assay. Metformin enhanced crocin-reduced cell viability (p < 0.001, compared to non-treated cells) in a time- and concentration-dependent manner (g–i). Cells cultured and treated with crocin (IC50 concentration) in the absence and presence of metformin (0–16 mM; 24–72 h). Crocin augmented metformin-decreased cell viability (p < 0.001, compared to non-treated cells) in a time- and concentration-dependent manner (j–l). Cells cultured and treated metformin (IC50 concentration) with and without crocin (0–4 mM; 24–72 h). *p < 0.05, **p < 0.01, ***p < 0.001; n = 3, all p values evaluated by comparison to non-treated cells (control group). Two signs – and + showed absence and presence of each component (IC50 concentration) in each MTT assay
Source publication
Metastatic breast cancer remains a serious health concern and numerous investigations recommended medicinal plants as a complementary therapy. Crocin is one of the known anticancer bio-component. Recently, the inhibitory effect of metformin has been studied on the various aspects of cancer. However, no study reported their combination effects on me...
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Citations
... The study revealed that saffron extract increased the expression of both genes, indicating a potential chemopreventive effect of saffron [31]. Crocin inhibits the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in breast cancer cells, resulting in an antiangiogenic effect [32,33]. Furthermore, Zarrineh et al. observed that triple-negative breast cancer cells (TNBC) exhibited heightened susceptibility to safranal, a non-toxic constituent of saffron. ...
... BC tumor progression and metastasis depend on angiogenesis and crocin exerts its anti-angiogenesis effects through the reduction of CD34 expression, in vivo and in vitro [32]. D34 is highly expressed in BC tumors and positively relates to Vascular Endothelial Growth Factor (VEGF), a key protein in angiogenesis [32,33]. However, the molecular mechanisms should be elucidated in the future. ...
Breast cancer (BC) is the most prevalent malignancy in women and the second
most common disease worldwide, affecting approximately one million individuals annually.
Despite the efficacy of conventional chemotherapy, medication resistance and adverse effects
limit its effectiveness, leading researchers to explore alternative treatments, including herbal remedies. Saffron, a well-known spice derived from the Crocus sativus L. plant, has shown
potential as a BC treatment. The active components of saffron exhibit anti-cancer properties
by inducing apoptosis, inhibiting cell division, and modulating signaling pathways implicated
in cancer development, such as PI3 K/AKT, NF-kB, and MAPK. Clinical findings suggest that
saffron can alleviate chemotherapy-induced symptoms, reduce serum tumor marker levels,
and enhance quality of life. Preliminary clinical trials are investigating the safety and efficacy
of saffron in treating BC, with recent evidence indicating that recommended doses of saffron
supplementation are well-tolerated and safe. This review provides an overview of the anti tumor effects of saffron and its unique chemical composition in BC. However, further research
and clinical studies are imperative to fully comprehend the potential of saffron in adjuvant
therapy for BC patients.
... downregulating VEGF and MMP9, however the authors did not elaborate on the precise molecular mechanism [19]. Met was demonstrated to enhance apoptosis and impede growth, invasion and EMT in ESCC cells, and it also strengthened the chemosensitivity of cisplatin in ESCC [20][21][22], verifying the regulatory functions of Met on ESCC development. ...
Introduction
Metformin (Met), a first-line oral anti-type 2 diabetes medication used globally, has been shown to hinder cancer progression via regulation of microRNAs (miRNAs). The previous reports on the relationship between Met use and the risk of esophageal squamous cell carcinoma (ESCC) have been controversial. Hence, this study aimed to explore how Met affected ESCC progression and the underlying molecular mechanism.
Material and methods
Cell migration, viability and invasiveness were respectively investigated using wound healing, CCK-8 and transwell assay. The expressions of miR-141-3p and Sciellin (SCEL) mRNA were examined by mean of quantitative real-time PCR (qRT-PCR) assay, and SCEL protein level was quantified by western blotting. In vivo tests of Met were performed on animals. The predicted binding of miR-141-3p to SCEL was more evidenced by dual-luciferase assay.
Results
Met treatment in ESCC cell largely impaired cell viability, migration and invasiveness. MiR-141-3p showed high expression in ESCC and was downregulated in ESCC cells after Met treatment. MiR-141-3p upregulation in Met-administered ESCC cells largely restored cell proliferative ability, migration and invasiveness. MiR-141-3p also attenuated the anti-tumor effect of Met in vivo. MiR-141-3p targeted SCEL whose expression was declined in ESCC, and SCEL expression was reinforced in ESCC cells after Met treatment. MiR-141-3p upregulation depleted SCEL expression and thus partially abolished the anti-cancer impacts of SCEL in Met-treated ESCC cells.
Conclusions
Met restrains the progression of ESCC by regulating the miR-141-3p/SCEL axis. Our findings clearly show that Met is associated with a lower risk of ESCC, and its anticancer effect could potentially be used to treat ESCC.
... Crocetin and crocetin di-glucose ester can scavenge free radicals, especially superoxide anions, and therefore they can protect cells from oxidative stress associated with many neurodegenerative disorders (23,24). Furthermore, experimentally, saffron extract and crocin have demonstrated activities in preventing and treating some malignancies (25,26). The objectives of this review are to present research progress in anticancer effects of saffron and crocin and the underlying mechanisms of action. ...
Background and objective:
Cancer is a major public health problem in the world, and it dramatically affects the life expectancy of patients and their quality of life. Natural products from botanicals could be beneficial in the prevention or treatment of a variety of cancers. Saffron (the extract of Crocus sativus) includes its major constituent, crocin, have been used as a folk medicine for a long time, and they have shown obvious cancer chemoprevention potential. The objectives of this review are to present the progress of research on the effects of saffron and crocin in cancer management and the underlying mechanisms of action.
Methods:
We searched publications in the English language, published between January 1, 1980 and September 30, 2022, of saffron and crocin on cancer through several search engines, i.e., PubMed, SciFinder and Web of Science.
Key content and findings:
In this article, we first summarize the phytochemical studies of this botanical. Then, we present the anticancer effects of saffron and crocin on different human cancer cells. Saffron and crocin showed obvious antiproliferative effects on human cancer cell lines, including colorectal cancer, breast cancer, lung cancer, prostate cancer, cervical cancer, leukemia, glioblastoma and rhabdomyosarcoma. Finally, the anticancer-related mechanisms of action are summarized, including cell cycle arrest at G0/G1 or G2/M phases, induction of caspase-dependent apoptosis, signaling pathway-linked tumor metabolism regulation, and adaptive immunity regulated inflammation of host immune responses.
Conclusions:
Previous studies related to saffron and crocin in cancer management have been reviewed and reported results have been analyzed. Clinical data suggest that saffron and crocin have beneficial effects to improve quality of life in cancer patients. Thus, saffron and crocin can be considered promising candidates for future clinical cancer studies.
... Furthermore, TNF-α was shown to induce the epithelial-to-mesenchymal transition in Human HCC cell lines [76]. It is noteworthy that high TNF-α expression levels were correlated with poor outcomes in HCC patients who received post-surgery adjuvant sorafenib [77]. This was explained by resistance to the sorafenib treatment. ...
This study investigated the therapeutic effects of the phytochemical crocin alone or in combination with sorafenib both in rats chemically induced with hepatocellular carcinoma (HCC) and in human liver cancer cell line (HepG2). Male rats were randomly divided into five groups, namely, control group, HCC induced group, and groups treated with sorafenib, crocin or both crocin and sorafenib. HCC was induced in rats with a single intraperitoneal injection of diethylnitrosamine (DEN), then 2-acetylaminofluorene (2-AAF). The HCC-induced rats showed a significant decrease in body weight compared to animals treated with either or both examined drugs. Serum inflammatory markers (C-reactive protein (CRP); interleukin-6 (IL-6); lactate dehydrogenase (LDH), and oxidative stress markers were significantly increased in the HCC group and were restored upon treatment with either or both of therapeutic molecules. Morphologically, the HCC-induced rats manifested most histopathological features of liver cancer. Treatment with either or both of crocin and sorafenib successfully restored normal liver architecture. The expression of key genes involved in carcinogenesis (TNFα, p53, VEGF and NF-κB) was highly augmented upon HCC induction and was attenuated post-treatment with either or both examined drugs. Treatment with both crocin and sorafenib improved the histopathological and inflammation parameters as compared to single treatments. The in vivo anti-cancer effects of crocin and/or sorafenib were supported by their respective cytotoxicity on HepG2 cells. Crocin and sorafenib displayed an anti-tumor synergetic effect on HepG2 cells. The present findings demonstrated that a treatment regimen with crocin and sorafenib reduced liver toxicity, impeded HCC development, and improved the liver functions.
... Zhao et al. (2021) with in vitro and in vivo studies demonstrated the angiogenesis inhibitory effect of crocin exerted through VEGF signaling pathway inhibition. Crocin inhibited VEGF expression and may be helpful as an attractive alternative option for cancer treatment, including breast cancer (Farahi et al., 2021;Saravani et al., 2020) and melanoma (Bakshi et al., 2018). ...
Crocin is a hydrophilic carotenoid that is synthesized in the flowers of the Crocus genus. Numerous in vitro and in vivo research projects have been published about the biological and pharmacological properties and toxicity of crocin. Crocin acts as a memory enhancer, anxiolytic, aphrodisiac, antidepressant, neuroprotective, and so on. Here, we introduce an updated and comprehensive review of crocin molecular mechanisms based on previously examined and mentioned in the literature. Different studies confirmed the significant effect of crocin to control pathological conditions, including oxidative stress, inflammation, metabolic disorders, neurodegenerative disorders, and cancer. The neuroprotective effect of crocin could be related to the activation of phosphatidylinositol 3‐kinase/protein kinase B (PI3K/AKT)/mammalian target of rapamycin (mTOR), Notch, and cyclic‐AMP response element‐binding protein signaling pathways. The crocin also protects the cardiovascular system through the inhibitory effect on toll‐like receptors. The regulatory effect of crocin on PI3K/AKT/mTOR, AMP‐activated protein kinase, mitogen‐activated protein kinases (MAPK), and peroxisome proliferator‐activated receptor pathways can play an effective role in the treatment of metabolic disorders. The crocin has anticancer activity through the PI3K/AKT/mTOR, MAPK, vascular endothelial growth factor, Wnt/β‐catenin, and Janus kinases‐signal transducer and activator of transcription suppression. Also, the nuclear factor‐erythroid factor 2‐related factor 2 and p53 signaling pathway activation may be effective in the anticancer effect of crocin. Finally, among signaling pathways regulated by crocin, the most important ones seem to be those related to the regulatory effect on the PI3K/AKT/mTOR pathway.
... Natural products such as Crocin are gaining importance as potential therapeutic approach in treatment and prevention of cancer. Most of these compounds have been investigated in experimental studies and clinical trials with promising results [77][78][79][80]. Studies have shown that Crocin possesses potential anti-cancer properties in different types of cancers such as leukemia, breast, colorectal, pancreatic, prostate cancers and etc., and may serve as adjuvant chemotherapy agent [79][80][81][82][83][84][85][86][87][88][89]. ...
... Most of these compounds have been investigated in experimental studies and clinical trials with promising results [77][78][79][80]. Studies have shown that Crocin possesses potential anti-cancer properties in different types of cancers such as leukemia, breast, colorectal, pancreatic, prostate cancers and etc., and may serve as adjuvant chemotherapy agent [79][80][81][82][83][84][85][86][87][88][89]. Also, a study showed that Crocin protected rats against MTX-induced hepatotoxicity by improving antioxidant defense system and attenuating oxidative stress and inflammation, indicating that it can be used as a protective agent against chemotherapeutic toxicity [90]. ...
Crocin, an active ingredient derived from saffron, is one of the herbal components that has recently been
considered by researchers. Crocin has been shown to have many anti-inflammatory and antioxidant properties,
and therefore can be used to treat various diseases. It has been shown that Crocin has a positive effect on the
prevention and treatment of cardiovascular disease, cancer, diabetes, and kidney disease. In addition, the role of
this substance in COVID-19 pandemic has been identified. In this review article, we tried to have a compre-
hensive review of the antioxidant and anti-inflammatory effects of Crocin in different diseases and different
tissues. In conclusion, Crocin may be helpful in pathological conditions that are associated with inflammation
and oxidative stress.
... As it concerns BC, several preclinical findings have demonstrated that metformin can interfere with cell proliferation and induce cell cycle arrest and apoptosis [25,82]. Moreover, metformin may modify the expression of main pro-tumorigenic genes and exert a synergic action with chemotherapeutics in BC cells [83][84][85][86][87]. Therefore, metformin has been suggested as a potential antitumoral agent in BC also considering the results of epidemiological studies in both diabetic and non-diabetic women [20,26,[88][89][90]. ...
Background
Metabolic disorders are associated with increased incidence, aggressive phenotype and poor outcome of breast cancer (BC) patients. For instance, hyperinsulinemia is an independent risk factor for BC and the insulin/insulin receptor (IR) axis is involved in BC growth and metastasis. Of note, the anti-diabetic metformin may be considered in comprehensive therapeutic approaches in BC on the basis of its antiproliferative effects obtained in diverse pre-clinical and clinical studies.
Methods
Bioinformatics analysis were performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project. The naturally immortalized BC cell line, named BCAHC-1, as well as cancer-associated fibroblasts (CAFs) derived from BC patients were used as model systems. In order to identify further mechanisms that characterize the anticancer action of metformin in BC, we performed gene expression and promoter studies as well as western blotting experiments. Moreover, cell cycle analysis, colony and spheroid formation, actin cytoskeleton reorganization, cell migration and matrigel drops evasion assays were carried out to provide novel insights on the anticancer properties of metformin.
Results
We first assessed that elevated expression and activation of IR correlate with a worse prognostic outcome in estrogen receptor (ER)-positive BC. Thereafter, we established that metformin inhibits the insulin/IR-mediated activation of transduction pathways, gene changes and proliferative responses in BCAHC-1 cells. Then, we found that metformin interferes with the insulin-induced expression of the metastatic gene CXC chemokine receptor 4 (CXCR4), which we found to be associated with poor disease-free survival in BC patients exhibiting high levels of IR. Next, we ascertained that metformin prevents a motile phenotype of BCAHC-1 cells triggered by the paracrine liaison between tumor cells and CAFs upon insulin activated CXCL12/CXCR4 axis.
Conclusions
Our findings provide novel mechanistic insights regarding the anti-proliferative and anti-migratory effects of metformin in both BC cells and important components of the tumor microenvironment like CAFs. Further investigations are warranted to corroborate the anticancer action of metformin on the tumor mass toward the assessment of more comprehensive strategies halting BC progression, in particular in patients exhibiting metabolic disorders and altered insulin/IR functions.
... These results demonstrated that crocin inhibited VEGF secretion by colon carcinoma cells in a concentration dependent manner. It was in agreement with the findings of Farahi et al., who revealed the potential for a combination therapy of metformin and crocin to suppress VEGF in breast cancer metastasis [51]. ...
Angiogenesis and metastasis play pivotal roles in the progression of cancer. We recently discovered that crocin, a dietary carotenoid derived from the Himalayan crocus, inhibited the growth of colon cancer cells. However, the exact role of crocin on the angiogenesis and metastasis in colorectal cancer remains unclear. In the present study, we demonstrated that crocin significantly reduces the viability of colon cancer cells (HT-29, Caco-2) and human umbilical vein endothelial cells (HUVEC), but was not toxic to human colon epithelial (HCEC) cells. Furthermore, pre-treatment of human carcinoma cells (HT-29 and Caco-2) with crocin inhibited cell migration, invasion, and angiogenesis in concentration -dependent manner. Further studies demonstrated that crocin inhibited TNF-α, NF-κB and VEGF pathways in colon carcinoma cell angiogenesis and metastasis. Crocin also inhibited cell migration, invasion, and tube formation in human umbilical vein endothelial cells (HUVEC) in a concentration -dependent manner. We also observed that crocin significantly reduced the secretion of VEGF and TNF-α induced activation of NF-kB by human colon carcinoma cells. In the absence of TNF-α, a concentration-dependent reduction in NF-kB was observed. Many of these observations were confirmed by in vivo angiogenesis models, which showed that crocin significantly reduced the progression of tumour growth. Collectively, these finding suggest that crocin inhibits angiogenesis and colorectal cancer cell metastasis by targeting NF-kB and blocking TNF-α/NF-κB/VEGF pathways.
... Several epidemiologic studies have correlated antihyperglycemic medication use with risk or outcomes of cancer, and have generally concluded that patients with type 2 diabetes treated with insulin and with sulfonylureas, which stimulate insulin secretion, have higher cancer incidence and mortality than those treated with metformin [218][219][220][221][222][223]. However, these results do not uniformly point to a direct link between insulin and cancer: despite strong preclinical evidence [208,224,225], the addition of metformin to chemotherapy for nonsmall cell lung cancer reduced hyperinsulinemia, but did not provide survival benefit [226]. In this same study, however, patients with high 18 F-Fluorodeoxyglucose uptake on their PET scans received a mortality benefit from metformin, suggesting certain glucose-dependent but insulin-independent effects in the tumor microenvironment. ...
For a century, since the pioneering work of Otto Warburg, the interwoven relationship between metabolism and cancer has been appreciated. More recently, with obesity rates rising in the U.S. and worldwide, epidemiologic evidence has supported a link between obesity and cancer. A substantial body of work seeks to mechanistically unpack the association between obesity, altered metabolism, and cancer. Without question, these relationships are multifactorial and cannot be distilled to a single obesity- and metabolism-altering hormone, substrate, or factor. However, it is important to understand the hormone-specific associations between metabolism and cancer. Here, we review the links between obesity, metabolic dysregulation, insulin, and cancer, with an emphasis on current investigational metabolic adjuncts to standard-of-care cancer treatment.
... In preclinical models of breast cancer, metformin ameliorated tumour angiogenesis by restraining HIF-1α-induced proangiogenic factors and abro-gating HER2-mediated VEGF secretion [45,46]. Metformin in combination with crocin suppressed metastatic breast cancer via VEGF downregulation [47], while cotreatment of metformin with the IGF-1R inhibitor and BMS-754807 exerted synergistic effects in inhibiting the proliferation of a panel of TNBC cell lines [48]. In the present study, metformin in combination with nimbolide was more efficacious in inhibiting AR/IGF-1R/PI3K/Akt signaling and angiogenesis in breast cancer cells as well as in endothelial cells potentiating its higher efficacy in combination chemotherapy than monotherapy. ...
Background & Objectives
There is growing evidence to implicate the insulin/IGF-1R/PI3K/Akt signaling cascade in breast cancer development and the central role of aldose reductase (AR) in mediating the crosstalk between this pathway and angiogenesis. The current study was designed to investigate whether nimbolide, a neem limonoid, targets this oncogenic signaling network to prevent angiogenesis in breast cancer.
Methods
Breast cancer cells (MCF-7, MDA-MB-231), EAhy926 endothelial cells, MDA-MB-231 xenografted nude mice, and tumour tissues from breast cancer patients were used for the study. Expression of AR and key players in IGF-1/PI3K/Akt signaling and angiogenesis was evaluated by qRT-PCR, immunoblotting, and immunohistochemistry. Molecular docking and simulation, overexpression, and knockdown experiments were performed to determine whether nimbolide targets AR and IGF-1R
Results
Nimbolide inhibited AR with consequent blockade of the IGF-1/PI3K/Akt and HIF-1/VEGF signaling circuit by influencing the phosphorylation and intracellular localisation of key signaling molecules. Downregulation of DNMT-1, HDAC-6, miR-21, HOTAIR, and H19 with upregulation of miR-148a/miR-152 indicated that nimbolide regulates AR and IGF-1/PI3K/Akt signaling via epigenetic modifications. Coadministration of nimbolide with metformin and the chemotherapeutic drugs tamoxifen/cisplatin displayed higher efficacy than single agents in inhibiting IGF-1/PI3K/Akt/AR signaling. Grade-wise increases in IGF-1R and AR expression in breast cancer tissues underscore their value as biomarkers of progression.
Conclusions
This study provides evidence for the anticancer effects of nimbolide in cellular and mouse models of breast cancer besides providing leads for new drug combinations. It has also opened up avenues for investigating potential molecules such as AR for therapeutic targeting of cancer.
