piperine and Breast-Neoplasms

Piperine (PIP) is an alkaloid found primarily in Piper longum, and this natural compound has been shown to exert effects on proliferation and survival against various types of cancer. In particular, PIP has potent inhibitory effects on breast cancer (BC), the most prevalent type of cancer in women worldwide. PIP targets numerous signaling pathways associated with the therapy of BC cells through the following mechanisms: (a) induction of arrest of the cell cycle and apoptosis; (b) alteration of the signaling protein expression; (c) reduction in transcription factors; and (d) inhibition of tumor growth. BC cells have the ability to resist conventional drugs, so one of the strategies is the combination of PIP with other phytochemicals such as paclitaxel, thymoquinone, hesperidin, bee venom, tamoxifen, mitoxantrone, piperlongumin, and curcumin. Nanotechnology-based drug encapsulation systems are currently used to enhance the release of PIP. This includes polymer nanoparticles, carbon nanotubes, and liposomes. In the present review, the chemistry and bioavailability of PIP, its molecular targets in BC, and nanotechnological strategies are discussed. Future research directions are also discussed to further understand this promising natural product.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Breast Neoplasms; Female; Humans; Nanotubes, Carbon; Piperidines; Polyunsaturated Alkamides

Despite the significant advances in screening methods for early diagnosis, breast cancer remains a global threat and continues to be the leading cancer diagnosed in women, requiring effective therapy. Currently, combination therapy has become the hallmark of breast cancer treatment due to the high incidence of tumor recurrence and disease progression after monotherapeutic treatments, including surgery, radiotherapy, endocrine therapy, and chemotherapy. Over the past decades, there has been considerable interest in studying the anticancer effect of bioactive phytochemicals from medicinal plants combined with these conventional therapies. The rationale for this type of therapy is to use combinations of drugs that work by different mechanisms, thereby decreasing the likelihood that cancer cells will develop resistance, and also reduce the therapeutic dose and toxicity of single treatments. Three agents have received great attention with regard to their anticancer properties: 1) piperine, a dietary phytochemical isolated from black pepper (Piper nigrum L.) and long pepper (Piper longum L.); 2) sulforaphane, an isothiocyanate mainly derived from cruciferous vegetables; and 3) thymoquinone, the active compound from black seed (Nigella sativa L.). This review focused on the combined effect of these 3 compounds on conventional cancer therapy with the objective of observing enhanced efficacy compared with single treatments. This review also highlights the importance of the nanoformulation of such bioactive phytochemicals that could enhance their bioavailability by providing an efficient targeted delivery system with a reduced systemic dose while resulting in a more efficient dosing at the target site.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Benzoquinones; Breast Neoplasms; Cell Line, Tumor; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Humans; In Vitro Techniques; Isothiocyanates; Patient Selection; Phytochemicals; Phytotherapy; Piperidines; Polyunsaturated Alkamides; Radiotherapy, Adjuvant; Sensitivity and Specificity; Sulfoxides

Non-homologous end joining, an important DNA-double-stranded break repair pathway, plays a prominent role in conferring resistance to radiotherapeutic agents, resulting in cancer progression and relapse.. The molecular players involved in the radio-sensitizing effects of piperine and many other phytocompounds remain evasive to a great extent. The study is designed to assess if piperine, a plant alkaloid can alter the radioresistance by modulating the expression of non-homologous end-joining machinery.. Estrogen receptor-positive/negative, breast cancer cells were cultured to understand the synergetic effects of piperine with radiotherapy. Cisplatin and Bazedoxifene were used as positive controls. Cells were exposed to γ- radiation using Low Dose gamma Irradiator-2000. The piperine effect on Estrogen receptor modulation, DNA-Damage, DNA-Damage-Response, and apoptosis was done by western blotting, immunofluorescence, yeast-based-estrogen-receptor-LacZ-reporter assay, and nuclear translocation analysis. Micronuclei assay was done for DNA damage and genotoxicity, and DSBs were quantified by γH2AX-foci-staining using confocal microscopy. Flow cytometry analysis was done to determine the cell cycle, mitochondrial membrane depolarization, and Reactive oxygen species generation. Pharmacophore analysis and protein-ligand interaction studies were done using Schrodinger software. Synergy was computed by compusyn-statistical analysis. Standard errors/deviation/significance were computed with GraphPad prism.. Using piperine, we propose a new strategy for overcoming acquired radioresistance through estrogen receptor-mediated modulation of the NHEJ pathway. This is the first comprehensive study elucidating the mechanism of radio sensitizing potential of piperine. Piperine enhanced the radiation-induced cell death and enhanced the expression and activation of Estrogen receptor β, while Estrogen receptor α expression and activation were reduced. In addition, piperine shares common pharmacophore features with most of the known estrogen agonists and antagonists. It altered the estrogen receptor α/β ratio and the expression of estrogen-responsive proteins of DDR and NHEJ pathway. Enhanced expression of DDR proteins, ATM, p53, and P-p53 with low DNA-PK repair complex (comprising of DNA-PKcs/Ku70/Ku80), resulted in the accumulation of radiation-induced DNA double-stranded breaks (as evidenced by MNi and γH2AX-foci) culminating in cell cycle arrest and mitochondrial-pathway of apoptosis.. In conclusion, our study for the first time reported that piperine sensitizes breast cancer cells to radiation by accumulating DNA breaks, through altering the expression of DNA-PK Complex, and DDR proteins, via selective estrogen receptor modulation, offering a novel strategy for combating radioresistance.

Topics: Alkaloids; Breast Neoplasms; Discoidin Domain Receptors; DNA; Estrogen Receptor alpha; Estrogens; Female; Humans; Receptors, Estrogen; Tumor Suppressor Protein p53

Anastrozole (ATZ) is a selective non-steroidal inhibitor widely used for the treatment of breast cancer in post-menopausal women. ATZ exerts its biological activity by inhibiting the enzyme aromatase, which is responsible for converting androgens to estrogens. Piperine (PIP), a natural alkaloid and the main component of black pepper, is used as a bioenhancer and for combating a variety of health issues ranging from upset stomach to dental problems.. ATZ has been reported to have poor water solubility and less bioavailability. The novel combination of ATZ and PIP was proposed to enhance the bioavailability of both the compounds. However, there are no reported studies on the simultaneous estimation of ATZ and PIP as well as stability studies to explore their potential interactions and degradation profiling.. A simple, accurate, precise, robust, sensitive, reliable, and economic analytical method for the simultaneous estimation of ATZ and PIP was developed using acetonitrile and water (60:40) as the mobile phase. Forced degradation studies and characterization of degradants were performed, and degradants were identified for molecular weight using LC-QTOF-ESI-MS; the structures of degradants were confirmed with mass accuracy measurements. The mechanism of each degradant has also been described in more detail in the manuscript.. A total of fourteen degradants were characterized and reported for their good human oral absorption. A precise, robust, accurate, cheap, and sensitive RP-HPLC-DAD simultaneous method for the estimation of ATZ and PIP has been developed. From the future point of view, there is huge scope to conduct pharmacological, pharmacodynamic, and drug-herb interaction studies based on this fruitful outcome. All the degradants may be screened against MDR-resistant breast cancer in the future to check their potential as a drug target.

Topics: Alkaloids; Anastrozole; Benzodioxoles; Breast Neoplasms; Drug Stability; Female; Humans; Piperidines; Polyunsaturated Alkamides; Water

Adipocyte-derived leptin activates multiple oncogenic signaling, leading to breast cancer cell progression and metastasis. Hence, finding effective strategies to inhibit the oncogenic effects of leptin would provide a novel approach for disrupting obesity-associated breast cancer. In the current study, we explored the role of piperine, a major plant alkaloid from

Topics: Alkaloids; Animals; Benzodioxoles; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Diet; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; MicroRNAs; Obesity; Piperidines; Polyunsaturated Alkamides; PPAR alpha

Breast cancer has become a worldwide threat, and chemotherapy remains a routine treatment. Patients are forced to receive continuous chemotherapy and suffer from severe side effects and poor prognosis. Natural alkaloids, such as piperine (PP) and piperlongumine (PL), are expected to become a new strategy against breast cancer due to their reliable anticancer potential. In the present study, cell viability, flow cytometry, and Western blot assays were performed to evaluate the suppression effect of PP and PL, alone or in combination. Data showed that PP and PL synergistically inhibited breast cancer cells proliferation at lower doses, while only weak killing effect was observed in normal breast cells, indicating a good selectivity. Furthermore, apoptosis and STAT3 signaling pathway-associated protein levels were analyzed. We demonstrated that PP and PL in combination inhibit STAT3 phosphorylation and regulate downstream molecules to induce apoptosis in breast cancer cells. Taken together, these results revealed that inactivation of STAT3 was a novel mechanism with treatment of PP and PL, suggesting that combination application of natural alkaloids may be a potential strategy for prevention and therapy of breast cancer.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dioxolanes; Female; Humans; MCF-7 Cells; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Signal Transduction; STAT3 Transcription Factor

Breast cancer is the leading cause of cancer mortality in women worldwide. Conventional cancer treatment is costly and results in many side effects. Dietary bioactive compounds may be a potential source for breast cancer prevention and treatment. In this scenario, the aim of this study was to investigate the effects of the bioactive compounds resveratrol, curcumin and piperine (R-C-P) on MCF-7 breast cancer cells and to associate them to Glyoxalase 1 (GLO1) activity. The findings indicate that R-C-P exhibits cytotoxicity towards MCF-7 cells. R-C-P decreased mitochondrial membrane potential (ΔΨm) by 1.93-, 2.04- and 1.17-fold, respectively. Glutathione and N-acetylcysteine were able to reverse the cytotoxicity of the assessed bioactive compounds in MCF-7 cells. R-C-P reduced GLO1 activity by 1.36-, 1.92- and 1.31-fold, respectively. R-C-P in the presence of antimycin A led to 1.98-, 1.65- and 2.16-fold decreases in D-lactate levels after 2 h of treatment, respectively. Glyoxal and methylglyoxal presented cytotoxic effects on MCF-7 cells, with IC

Topics: Alkaloids; Benzodioxoles; Breast Neoplasms; Curcumin; Female; Humans; Lactoylglutathione Lyase; MCF-7 Cells; Membrane Potential, Mitochondrial; Piperidines; Polyunsaturated Alkamides; Resveratrol

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Bee Venoms; Benzodioxoles; Biomarkers, Tumor; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Resistance, Multiple; Drug Synergism; Estrogen Receptor alpha; Female; Hesperidin; Humans; MCF-7 Cells; Piperidines; Polyunsaturated Alkamides; RNA, Messenger; Tamoxifen; Up-Regulation

P-glycoprotein (P-gp) efflux is the major cause of multidrug resistance (MDR) in tumors when using anticancer drugs, moreover, poor bioavailability of few drugs is also due to P-gp efflux in the gut. Rapamycin (RPM) is in the clinical trials for breast cancer treatment, but its P-gp substrate property leads to poor oral bioavailability and efficacy. The objective of this study is to formulate and evaluate nanoparticles of RPM, along with a chemosensitizer (piperine, PIP) for improved oral bioavailability and efficacy. Poly(d,l-lactide-co-glycolide) (PLGA) was selected as polymer as it has moderate MDR reversal activity, which may provide additional benefits. The nanoprecipitation method was used to prepare PLGA nanoparticles with particle size below 150 nm, loaded with both drugs (RPM and PIP). Prepared nanoparticles showed sustained in vitro drug release for weeks, with initial release kinetics of zero order with non-Fickian transport, subsequently followed by Higuchi kinetics with Fickian diffusion. An everted gut sac method was used to study the effect of P-gp efflux on drug transport. This reveals that the uptake of the RPM (P-gp substrate) has been increased in the presence of chemosensitizer. Pharmacokinetic studies showed better absorption profile of RPM from polymeric nanoparticles compared to its suspension counterpart and improved bioavailability of 4.8-folds in combination with a chemosensitizer. An in vitro cell line study indicates higher efficacy of nanoparticles compared to free drug solution. Results suggest that the use of a combination of PIP with RPM nanoparticles would be a promising approach in the treatment of breast cancer.

Topics: Alkaloids; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Availability; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Lactic Acid; Nanoparticles; Piperidines; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polyunsaturated Alkamides; Sirolimus

Curcumin is a potential agent for both the prevention and treatment of cancers. Curcumin treatment alone, or in combination with piperine, limits breast stem cell self-renewal, while remaining non-toxic to normal differentiated cells. We paired fluorescence-activated cell sorting with RNA sequencing to characterize the genome-wide changes induced specifically in normal breast stem cells following treatment with these compounds. We generated genome-wide maps of the transcriptional changes that occur in epithelial-like (ALDH+) and mesenchymal-like (ALDH-/CD44+/CD24-) normal breast stem/progenitor cells following treatment with curcumin and piperine. We show that curcumin targets both stem cell populations by down-regulating expression of breast stem cell genes including ALDH1A3, CD49f, PROM1, and TP63. We also identified novel genes and pathways targeted by curcumin, including downregulation of SCD. Transient siRNA knockdown of SCD in MCF10A cells significantly inhibited mammosphere formation and the mean proportion of CD44+/CD24- cells, suggesting that SCD is a regulator of breast stemness and a target of curcumin in breast stem cells. These findings extend previous reports of curcumin targeting stem cells, here in two phenotypically distinct stem/progenitor populations isolated from normal human breast tissue. We identified novel mechanisms by which curcumin and piperine target breast stem cell self-renewal, such as by targeting lipid metabolism, providing a mechanistic link between curcumin treatment and stem cell self-renewal. These results elucidate the mechanisms by which curcumin may act as a cancer-preventive compound and provide novel targets for cancer prevention and treatment.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Separation; Curcumin; Female; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Piperidines; Polyunsaturated Alkamides; Sequence Analysis, RNA; Stearoyl-CoA Desaturase; Stem Cells

Targeting Survivin, as an inhibitor of apoptosis and a regulator of cell division, has become a worldwide controversial issue. Piperine as a pungent alkaloid has been identified as the most potent adjuvant at enhancing the efficacy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based therapies in triple-negative breast cancer (TNBC) cells in vitro and in vivo, which might be mediated through inhibition of Survivin. In this work, the binding energies, inhibition constants and binding modes of a group of previously synthesized Piperine derivatives at the binding site of Survivin have been studied using molecular docking tools and the best compounds with minimum binding energies are proposed as potential drugs for the inhibition of Survivin. A comprehensive SAR analysis has been done on the results that can be used for designing new Piperine analogs with higher efficacy. Molecular docking computations also show that the studied compounds can bind to BIR domain of Survivin in the same binding site as that of Smac/DIABLO with a suitable binding energy. This binding may result in the segregation of Smac/DIABLO in the cytosol and subsequently free Smac/DIABLO molecules could be available for binding with inhibitors of apoptosis to initiate caspase mediated apoptosis.

Topics: Alkaloids; Benzodioxoles; Binding Sites; Breast Neoplasms; Female; Humans; Inhibitor of Apoptosis Proteins; Molecular Docking Simulation; Neoplasm Proteins; Piperidines; Polyunsaturated Alkamides; Survivin

Piperine is a bioactive component of black pepper, Piper nigrum Linn, commonly used for daily consumption and in traditional medicine. Here, the molecular mechanisms by which piperine exerts antitumor effects in HER2-overexpressing breast cancer cells was investigated. The results showed that piperine strongly inhibited proliferation and induced apoptosis through caspase-3 activation and PARP cleavage. Furthermore, piperine inhibited HER2 gene expression at the transcriptional level. Blockade of ERK1/2 signaling by piperine significantly reduced SREBP-1 and FAS expression. Piperine strongly suppressed EGF-induced MMP-9 expression through inhibition of AP-1 and NF-κB activation by interfering with ERK1/2, p38 MAPK, and Akt signaling pathways resulting in a reduction in migration. Finally, piperine pretreatment enhanced sensitization to paclitaxel killing in HER2-overexpressing breast cancer cells. Our findings suggest that piperine may be a potential agent for the prevention and treatment of human breast cancer with HER2 overexpression.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Apoptosis; Benzodioxoles; Breast Neoplasms; Caspase 3; Female; Gene Expression Regulation, Neoplastic; Humans; p38 Mitogen-Activated Protein Kinases; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Receptor, ErbB-2; Signal Transduction

Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G(1)/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induced angiogenic activity by rat aorta explants and breast cancer cell-induced angiogenesis in chick embryos. Although piperine binds to and activates the cation channel transient receptor potential vanilloid 1 (TRPV1), its effects on endothelial cells did not involve TRPV1 since the antiproliferative effect of piperine was not affected by TRPV1-selective antagonists, nor did HUVECs express detectable TRPV1 mRNA. Importantly, piperine inhibited phosphorylation of Ser 473 and Thr 308 residues of Akt (protein kinase B), which is a key regulator of endothelial cell function and angiogenesis. Consistent with Akt inhibition as the basis of piperine's action on HUVECs, inhibition of the phosphoinositide-3 kinase/Akt signaling pathway with LY-294002 also inhibited HUVEC proliferation and collagen-induced angiogenesis. Taken together, these data support the further investigation of piperine as an angiogenesis inhibitor for use in cancer treatment.

Topics: Alkaloids; Angiogenesis Inhibitors; Animals; Aorta; Benzodioxoles; Breast Neoplasms; Cell Movement; Cell Proliferation; Chick Embryo; Chromones; Drug Screening Assays, Antitumor; Female; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Male; Morpholines; Neovascularization, Pathologic; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Rats, Wistar; S Phase; Serine; Threonine; TRPV Cation Channels

To investigate the effects of piperine, a major pungent alkaloid present in Piper nigrum and Piper longum, on the tumor growth and metastasis of mouse 4T1 mammary carcinoma in vitro and in vivo, and elucidate the underlying mechanisms.. Growth of 4T1 cells was assessed using MTT assay. Apoptosis and cell cycle of 4T1 cells were evaluated with flow cytometry, and the related proteins were examined using Western blotting. Real-time quantitative PCR was applied to detect the expression of matrix metalloproteinases (MMPs). A highly malignant, spontaneously metastasizing 4T1 mouse mammary carcinoma model was used to evaluate the in vivo antitumor activity. Piperine was injected into tumors every 3 d for 3 times.. Piperine (35-280 μmol/L) inhibited the growth of 4T1 cells in time- and dose-dependent manners (the IC(50) values were 105 ± 1.08 and 78.52 ± 1.06 μmol/L, respectively, at 48 and 72 h). Treatment of 4T1 cells with piperine (70-280 μmol/L) dose-dependently induced apoptosis of 4T1 cells, accompanying activation of caspase 3. The cells treated with piperine (140 and 280 μmol/L) significantly increased the percentage of cells in G(2)/M phase with a reduction in the expression of cyclin B1. Piperine (140 and 280 μmol/L) significantly decreased the expression of MMP-9 and MMP-13, and inhibited 4T1 cell migration in vitro. Injection of piperine (2.5 and 5 mg/kg) dose-dependently suppressed the primary 4T1 tumor growth and injection of piperine (5 mg/kg) significantly inhibited the lung metastasis.. These results demonstrated that piperine is an effective antitumor compound in vitro and in vivo, and has the potential to be developed as a new anticancer drug.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Benzodioxoles; Breast; Breast Neoplasms; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 13; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Piper; Piperidines; Polyunsaturated Alkamides

The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor cells through the dysregulation or acquisition of self-renewal. In order to determine whether the dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and malignant breast stem cells, we examined the effects of these compounds on mammosphere formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt signaling. Mammosphere formation assays were performed after curcumin, piperine, and control treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells, selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 microM and completely at 10 microM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 microM and completely at 10 microM. Curcumin and piperine separately, and in combination, inhibit breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds could be potential cancer preventive agents. Mammosphere formation assays may be a quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment can be a mechanistic biomarker for use in human clinical trials.

Topics: Aldehyde Dehydrogenase; Alkaloids; Antineoplastic Combined Chemotherapy Protocols; Benzodioxoles; Breast; Breast Neoplasms; Cell Differentiation; Cell Proliferation; Cells, Cultured; Curcumin; Female; Humans; Immunoenzyme Techniques; Neoplastic Stem Cells; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Wnt Proteins

Topics: Alkaloids; Anticarcinogenic Agents; Benzodioxoles; Breast; Breast Neoplasms; Clinical Trials as Topic; Curcumin; Diet; Estrogen Antagonists; Humans; Piperidines; Polyunsaturated Alkamides; Stem Cells