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Cancer is a genetic disease characterized by unregulated growth and dissemination of malignantly transformed neoplastic cells. The process of cancer development goes through several stages of biochemical and genetic alterations in a target cell.

Several dietary alkaloids have been found to inhibit the molecular events and signaling pathways associated with various stages of cancer development and therefore are useful in cancer chemoprevention. Cancer chemoprevention has long been recognized as an important prophylactic strategy to reduce the burden of cancer on health care system.

Cancer chemoprevention assumes the use of one or more pharmacologically active agents to block, suppress, prevent, or reverse the development of Hast bet pungen av 5 aring cancer. Piperine is an active alkaloid with an excellent spectrum of therapeutic activities such as anti-oxidant, anti-inflammatory, immunomodulatory, anti-asthmatic, anti-convulsant, anti-mutagenic, antimycobacterial, anti-amoebic, and anti-cancer activities. In this article, we made an attempt to sum up the current knowledge on piperine that supports the chemopreventive potential of this dietary phytochemical.

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Many mechanisms have been purported to understand the chemopreventive action of piperine. Piperine has been reported to inhibit the proliferation and survival of many types of cancer cells through its influence on activation of apoptotic signaling and inhibition of cell cycle progression. Piperine is known to affect cancer cells in variety of other ways such as influencing the redox homeostasis, inhibiting cancer stem cell CSC self-renewal and modulation of ER stress and autophagy.

Piperine can modify activity of many enzymes and transcription factors to inhibit invasion, metastasis, and angiogenesis. Piperine is a potent inhibitor of p-glycoprotein P-gp and has a significant effect on the drug metabolizing enzyme DME system. Because of its inhibitory influence on P-gp activity, piperine can reverse multidrug resistance MDR in cancer cells and acts as bioavailability enhancer for many chemotherapeutic agents.

In this article, we emphasize the Hast bet pungen av 5 aring of piperine as a promising cancer chemopreventive agent and the knowledge we collected in this review can be applied in the strategic design of future researches particularly human intervention trials with piperine.

Cancer is a deadly disease affecting human health in today's world and causes a huge economic and human loss throughout the world Siegel et al. Several genetic, environmental, and lifestyle factors can contribute to a higher risk of cancer development in humans.

The lifestyle factors often associated with cancer development include unhealthy diet such as processed foods, red meatcigarette smoking, environmental carcinogens, ultraviolet UV exposure, stress, obesity, and physical inactivity Anand et al. Effectiveness of cancer prevention depends on the identification of potential risk factors and understanding how, at the molecular level, these factors trigger cancer initiation and progression Sloan and Gelband, A better understanding of the signaling pathways and molecular events involved in cancer initiation can be acquired from following up patients with a higher risk for a specific type of cancer.

Many dietary components owing to Hast bet pungen av 5 aring potential carcinogenic and mutagenic properties can initiate tumor growth in animal models and transform normal cells into mass of neoplastic cells Zielinski, Phytochemicals, the non-nutritive components in the plant-derived diet, have recently garnered considerable attention for their role in prevention of cancer Landis-Piwowar and Iyer, The World Health Organization WHO has laid down certain dietary guidelines to help people minimize the risk of acquiring a particular cancer type.

Nutrigenomics can substantially refine our understanding of the complex interactions of phytochemicals with cancer cells and their potential role in prevention of cancer Braicu et al. Nevertheless, cancer prevention by dietary phytochemicals is accepted as an inexpensive, readily applicable and accessible approach. Therefore, it is advisable to educate people regarding the consumption of phytochemicals as a cancer-preventive strategy Pem and Jeewon, Dietary phytochemicals have long Hast bet pungen av 5 aring used for their potential as cancer preventive agents, which has lead to the development of cancer chemoprevention Wattenberg, Many of these phytochemicals have entered into intervention trials for their potential role in cancer chemoprevention Hosseini and Ghorbani, Piperine, a widely consumed dietary phytochemical, has shown cancer preventive properties both in cell cultures and animal models.

In this review article, we discuss the molecular mechanisms underlying the chemopreventive action of piperine and their relevance to human health.

The characteristic pungency and biting taste of pepper is due high content of piperine in it. Piperine has been exploited for many therapeutic purposes in the past and is anticipated to remain so in the future. Piperine is an important dietary phytochemical due to its presence in spicy foods as well as its pharamacological activities antiinflammatory, antimetastatic, anti-cancer, larvicidal, leishmanicidal, Hast bet pungen av 5 aring, antimycobacterial, and antiparasitic activities Freire-de-Lima et al.

Piperine was first separated from the extracts of pepper by Hans Christian Orsted in Gorgani et al. Piperine, along with its isomers isopiperine, chavicine, and isochavicine, belongs to the family of alkaloids Gorgani et al. Alkaloids constitute a group of natural occurring organic compounds that contain a ring structure and a basic nitrogen atom.

By and large, the nitrogen atom is situated inside the heterocyclic Hast bet pungen av 5 aring structure Cordell, Alkaloids have long been used as a reservoir Hast bet pungen av 5 aring drug discovery infrastructure and, some of these alkaloids have already been approved by the US Food and Drug Administration FDAsuch as camptothecin, a famous inhibitor of topoisomerase I, and vinblastine, which interacts with tubulin leading to mitotic catastrophe Lu et al.

The cancer preventive impacts of piperine against a few sorts of cancer-causing agents, for example, 7,dimethyl benz a anthracene and benzo a pyrene, demonstrate its potential as a cancer chemopreventive agent Selvendiran et al.

To better understand the mechanistic role of piperine in cancer chemoprevention, it will be useful to know how cancer develops. Piperine is an alkaloid containing a heterocyclic ring structure and a basic nitrogen atom. Nitrogen atom is located inside the ring structure. Cancer development is a slow and dynamic process in which a genetically altered cell undergoes malignant transformation to form a mass of neoplastic cells Cooper, Cancer development consists of atleast three separate but interconnected stages: Although cancer is a difficult to treat disease, it can be prevented Anand et al.

Majority of cancer chemopreventive agents are present in fruits, vegetables and spices and can influence cancer cells in variety of ways Rajesh et al.

However, validation of the mechanisms by which these components suppress cancer is obligatory before they can be prescribed for consideration in dietary servings or before they can be tried in human intervention trials Greenwald, Piperine, a pharmacologically safe alkaloid, has been studied extensively for its chemopreventive properties Gorgani et al. In this review, we will discuss the concept of cancer chemoprevention and analyzed the recent advances in chemopreventive action of piperine at the molecular, cellular and organism level which can be useful in design of future researches and exploration of new molecular targets for therapeutic intervention.

Critical steps in the process of cancer development. Cancer initiates with the transformation of a normal cell into an initiated cell, which undergoes tumor promotion to form preneoplastic cells and finally progress to neoplastic cells. Cancer chemopreventive agents can interfere with initiation blocking agents or later steps of this multi-stage process suppressing agents.

Cancer chemoprevention encourages the use of natural or synthetic agents to interrupt the process of cancer development by blocking or suppressing specific molecular events and signaling pathways associated with cancer development Landis-Piwowar and Iyer, Blocking agents are inhibitors of tumor initiation. Usually, combination chemopreventive strategy is preferred over single-agent chemoprevention. Combination chemopreventive approach utilizes multiple chemopreventive agents at low doses to achieve maximum chemopreventive efficacy with minimum toxicity Chen and Malhotra, Mechanism of cancer chemoprevention.

Cancer chemopreventive agents can inhibit the metabolic conversion of procarcinogens to Hast bet pungen av 5 aring ultimate reactive intermediates group I blocking agents and their subsequent interaction with DNA, RNA, and proteins group III blocking agents.

Alternatively, blocking agents can stimulate the detoxification of carcinogens group II blocking agentsleading to their removal from the body. Other chemopreventive agents suppressing agents can suppress the later steps promotion, progression of cancer development.

Some chemopreventive agents Hast bet pungen av 5 aring behave as both blocking and suppressing agents. Clinically, cancer chemoprevention has been classified as primary, secondary, and tertiary prevention. Primary chemoprevention is implemented to block the development of premalignant lesions, whereas secondary chemoprevention concentrates on suppressing the progression of these lesions to cancer, and tertiary chemoprevention aims to prevent the relapse or dissemination of a primary cancer Greenwald, ; Steward and Brown, The ultimate goal of all forms of chemopreventive approaches is to decrease the rate of cancer incidence and cancer related deaths Wattenberg, Nevertheless, there are several limitations that hamper the clinical use of chemopreventive agents such as the monetary costs and time required for directing epidemiological studies; "Hast bet pungen av 5 aring" and purification of these molecules; pharmacokinetic and pharmacodynamic properties of these agents e.

Notably, piperine is profoundly hydrophobic and practically insoluble in water, which might hamper its use in clinics. Given that piperine is consumed widely as an integral part of human diet; piperine can be administered to human subjects with minimum toxicity and assessed for clinical efficacy. The Hast bet pungen av 5 aring of cancer chemoprevention was recognized early in human history with identification and development of raloxifene and tamoxifen for breast cancer prevention and a series of agents that can cure cutaneous preneoplastic lesions Kelloff et al.

The first translational study of a potential chemopreventive agent was conducted using cis retinoic acid a derivative of vitamin A which showed a significant size reduction in premalignant lesions of oral leukoplakia and prevented primary head-and-neck tumors Lippman and Hong, The main chemopreventive mechanisms of action of piperine include activation of apoptotic signaling cascades, inhibition of cell proliferation, cell cycle arrest, alterations in redox homeostasis, modulation of ER stress and autophagy, inhibition of angiogenesis, induction of detoxification enzymes, and sensitization of tumors to radiotherapy and chemotherapy Manayi et al.

The aforementioned mechanisms of action of piperine reveal that piperine can contribute significantly to cancer chemoprevention.

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Many chemopreventive agents are known to induce apoptosis and are used to retard tumor growth. Apoptosis is usually executed through two major pathways: At the molecular level, piperine can influence many effector proteins engaged in apoptotic process and can activate both intrinsic and extrinsic pathways of apoptosis.

Piperine suppressed the tumor development and metastasis in a mouse 4T1breast tumor model Lai et al. Piperine treatment markedly decreased tumor growth in nude mice model xenografted with the androgen dependent PC3 and androgen independent LNCaP, DU prostate cancer cells Samykutty et al. Therefore, piperine can be utilized as a potential chemopreventive agent in the management of prostate cancer. Piperine is a potent inhibitor of cancer-associated angiogenesis and tumor invasiveness Doucette et al.

These studies indicate that piperine might have a role in modulating signaling networks associated with epithelial-to-mesenchymal transition EMTa process that regulates metastasis, cancer stem cell CSC self-renewal and Hast bet pungen av 5 aring heterogeneity Chaffer et al. Piperine is also a very good antimetastatic agent against lung carcinogenesis "Hast bet pungen av 5 aring" by B16F10 mouse melanoma cells in mice Pradeep and Kuttan, and stifled PMA-induced invasiveness of human fibrosarcoma HT cells Hwang et al.

Oral supplementation of piperine markedly reduced the DNA damage and DNA-protein crosslinks in experimental model of benzo a pyrene induced lung carcinogenesis Selvendiran et al. Piperine appears to extend its chemopreventive effects against lung carcinogenesis through the modulation of serum and tissue glycoprotein levels, which are one of the key biomarkers of neoplastic transformation Selvendiran et al.

Inside it's long and narrow,...

Therefore, piperine can serve as a promising chemopreventive agent for human breast cancer with HER2 overexpression Do et al. Piperine is also an inhibitor of survivin and this information has been exploited for therapeutic intervention of neuroblastoma, an embryonically derived tumor Muthukumar and Vanisree, ; Sattarinezhad et al.

Survivin is an important anti-apoptotic protein that is significantly up-regulated in neuroblastoma Hagenbuchner et al. Piperine can inhibit the activity of enzyme EGFR tyrosine kinase, which is one of the key targets of potential chemopreventive agents Kelloff et al.

Recent evidences have shown that piperine can be used to suppress cancer development by targeting human G-quadruplex DNA sequences Tawani et al. G-quadruplex DNA structures are four stranded DNA structures that are generated by square planar arrangement of G-quartets during DNA metabolism and play vital role in regulation of cellular processes Hast bet pungen av 5 aring might contribute to cancer "Hast bet pungen av 5 aring." Piperine binds with high affinity to G-quadruplex DNA and in particular to G-quadruplex structure formed at c-myc promoter region Tawani et al.

The ability of piperine to bind G-quadruplexe structures makes it useful as a potent chemopreventive agent for cancers with aberrations in DNA metabolism.

Piperine triggers apoptosis and causes cell cycle arrest. Piperine is a pro-oxidant agent and can stimulate the formation of reactive oxygen species ROS in many types of cancer cells. ROS triggers the depolarization of mitochondrial membrane potential MMPleading to release of cytochrome c, activation of caspases, and induction of apoptosis.

Piperine can activate both intrinsic and extrinsic pathways of apoptosis.

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In addition to inducing caspases mediated apoptosis, piperine can inhibit cell proliferation via cell cycle arrest. At the G1 phase, piperine halts cell cycle progression through downregulation of cyclin D and upregulation of p Piperine upregulates the expression of p Reactive oxygen species ROSfree radicals, and ultimate reactive forms produced from metabolic activation of procarcinogens are known to assume a critical role in cancer development Liou and Storz, ROS are also generated from non-enzymatic activity of electron transport chain in mitochondria Murphy, Piperine mediated redox changes can influence cellular physiology in variety of ways which may be cell or tissue specific as well as dose dependent.

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