We focused on genes determining the response of tumor cells to apigenin. Our results do not suggest that the ABC transporters ABCB1 and ABCB5 may play a role for apigenin resistance. Multidrug resistance caused by P-glycoprotein (MDR1/ABCB1) represents a major impediment of cancer chemotherapy. P-glycoprotein is expressed in many tumor types being either inherently resistant to anticancer drugs or acquiring resistance during chemotherapy [26].
ABCB5 is highly expressed in melanoma [23] and confers multidrug resistance to anthracyclines and taxanes [24,27]. This ABC transporter can also be found in other tumor types and its expression is correlated with the stem cell marker CD133 [25].
The sensitivity of multidrug-resistant ABCB1- or ABCB5-expressing cells towards apigenin implies that apigenin may improve treatment success of tumors, which do not respond to standard anticancer drugs anymore. Another ABC transporter mediating MDR and with relevance for worse treatment outcome patients is BCRP/ABCG2. A lack of correlation of log10IC50 values for apigenin was not only observed to ABCB1 and ABCB5, but also to ABCG2 (data not shown). This indicates that the clinically most relevant ABC transporters do not play a role for resistance of tumor cells towards apigenin.
Although apigenin is not a substrate of P-glycoprotein, it is able to inhibit the transport of other P-glycoprotein substrates and modulate drug resistance [28]. Apigenin may bind to P-glycoprotein without being transported. Binding of apigenin disturbs the outward transport of substrates leading to increased intracellular accumulation of anticancer drugs and improved cell killing as shown for doxorubicin in resistant uterine sarcoma cells (MES-SA/Dx5) [29]. Furthermore, a...
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...nin log10IC50 values. Tubulin is a well-known target for established drugs such as Vinca alkaloids or taxanes [67]. Apigenin also interacts with tubulin and disturbs microtubules [68]. These data fit well to an association between TTLL9 expression and cellular response to apigenin and it can be assumed that the microtubule machinery might be a determinant for apigenin sensitivity in cancer cells.
Summarizing the results of us and other authors, it is obvious that apigenin exert cytotoxic activity towards cancer cells by multiple rather than by single mechanisms (Figure 4). Phytochemicals are known to frequently exert multiple functions [69]. During evolution of life, bioactive compounds with multifactorial modes of action to deter viruses, bacteria or herbivores were superior to monospecific substances, which can easily be subject to the development of resistance.
Montaner, B. and Perez-Tomas, R. 2001. Prodigiosin-induced apoptosis in human colon cancer cells. Life sciences, 68 (17), p. 2025-2036.
The concept of tumor heterogeneity being related to the course of the disease and clinical outcome in cancer patients draws additional attention in the era of personalized medicine (1). Current cancer treatment strategies are based on the site of origin of the primary tumor. However, it was shown that tumors developed from distinct cell types differ in their prognosis and response to cytotoxic therapies (2...
The first experiment reviewed was titled “MRP3: a molecular target for human glioblastoma multiforme immunotherapy” and was carried out at Duke University Medical Center in Durham, North Carolina by-Kuan et al’s (2010). Their study was conducted to identify brain tumor markers that are needed for prognostics from immunotherapeutic approaches. From series of analysis they found multidrug-resistance protein 3 (MRP3) to be a candidate marker of GBM [2]. After discovering a potential molecular therapeutic target Kuan et al. hypothesize that there would be evidence that MRP3is potentially a good target in immunotherapy for those with GBM [2].
Rockmann, H., and D. Schadendorf. "Drug Resistance in Human Melanoma: Mechanisms and Therapeutic Opportunities" Onkologie 26 (December 2003): 581–587.
Cancer in one way or another touches all of us, whether as a patient or through the diagnosis of the people you love around you. Millions of patients who are faced with cancer are depending on oncologists everywhere to cure cancer so others will not suffer like they had to. Optimistically, sooner rather than later this international problem will come to an end. There are a number of drug companies that have been coming out with cancer treatment drugs. “Oncology has been one of the hottest and most active therapeutic areas for drug development, drug makers may want to take note of a finding that new cancer drugs have proven far more difficult to gain approval than medicines for infectious and autoimmune diseases.” (nature.com) Unfortunately, these drugs cannot cure the cancer but it sure makes it a load easier o...
Cancer has been seen in humans as one the most potentially fatal disease for thousands of years and only in the recent couple of hundred years have we discovered that most information necessary to bring us to today’s understanding and knowledge (Kenny 2007, Weinberg 1996) was achieved by extensive research of cells, DNA, and epidemiology studies. As we know, currently cancer is acknowledged as having over a hundred different diseases, and is known to be the result of mutations of the genes and almost similar DNA which are responsible for the amount of cell division and production (Kenny 2007). Restraint of cell growth modulators can be a direct lead and result of certain tumours being developed and subsequently allow these tumours to acquire the ability to attack and occupy the bloodstream and essentially be able to travel via the bloodstream to other parts and organs in human bodies which is known as metastasis (Loeb et Al 2003). Once this has occurred , the cancer is then categorized as malicious and becomes a dangerous and serious threat to the carrier (Weinberg 1996). In this essay I will describe and explain the process of this and how our genes mutate and lead to metastasis of cancer cells.
The Hallmarks of Cancer written by Doughlas Hanahan and Robert A. Weinberg proposed the underlying principles and the essential characteristics of the development of human tumors. This article distilled all the existing research to depict the fundamental characteristics of cancer. Hanahan and Weinberge proposed six hallmarks shared among all cancers mentioned in this article includes supporting proliferative signaling, evading growth suppressor, resisting cell death, enabling replicative immortality, sustaining angiogenesis, and tissue invasion and metastasis. Four emerging hallmarks are also introduced in this article, depicting the current 10 underlying principles shared by cancerous cells. Hanahan and Weinberg also provided specific examples of potential mechanisms for the hallmarks. All of the mechanisms of hallmarks of cancer must be fulfilled in the development of cancerous cells.
The American Cancer Society publishes current advances made in cancer research on their website. Many of the exciting discoveries about how best to treat the disease focus on the genetic aspects associated with certain types of cancer. In addition, treatments aimed at genetic solutions to cancer may be more effective and may cause fewer adverse side effects than traditional cancer treatments (American Can...
The future of oncotherapy relies on using recent discoveries about the cause of cancer to establish more specific and effective treatments. Cancer is caused by gene mutations that lead to the hallmarks of cancer, like uncontrollable growth. For example, Axel Ullrich and Dennis Slamon discovered that a cell surface growth receptor, Her-2, is overexpressed on the cell surface membrane in a portion of breast cancers (Mukherjee 416). Antibodies or inhibitors to Her-2, or any other protein that a cancer cell requires to live, provides a great source for cancer treatment. The results of many clinical trials showed that the “overall survival in women treated with Herceptin was increased by 33% - a magnitude unprecedented in the history of chemotherapy for Her-2 positive cancer” (Mukherjee 428). Discovery of a mutated gene in a cancer cell led to creating an inhibitor of that protein and resulted in specific and effective treatment for cancer. Cancer treatment has come a long way since the 1980s, especially in this use of molecular biology and chemical design in creating small molecular inhibitors against the cellular pathways that the tumor exploits. The future of oncotherapy lies in sequencing a patient’s tumor to discover the mutations that make the particular tumor cancerous, and then creating a drug to inhibit that specific gene or protein, thus killing the tumor cell and
In vitro: The proliferation of tumor antigen CA-125 expression in ovarian cancer cells was not affected by ALCAR.
Conventional chemotherapeutic agents are usually administered via the intravenous (i.v.) route. However, the major drawbacks with i.v. administration of therapeutic agents is their widespread distribution throughout the body via the bloodstream affecting both malignant and rapidly dividing normal cells in the bone marrow [64]. This leads to increased side effects, higher patient risks, decreased biodistribution of drugs to the tumor site and development of multidrug resistance against the chemotherapeutic drugs by the cancer cells[65]. Chemotherapeutics are also rapidly cleared by the reticuloendothelial system (RES), which results in a reduced amount of drugs reaching the target site leading to decreased efficacy [66]. Most of the anticancer drugs are hydrophobic and due to their toxicity to normal and cancer cells, they have to be developed in a formulation to be delivered via an i.v. route [67].
Identification of CSCs is widely done by the side population approach which involves elimination of Hoechst 33342. Hoechst 33342, a fluorescent DNA-binding dye, preferentially binds to A-T rich regions of tumourigenic cells. These SPs express high levels of the ATP-binding cassette (ABC) transporter superfamily (e.g. MDR1, MRP1, ABCB5, ABCG2) that facilitates the efflux of this dye and other drugs (Zhang et al., 2009).
Yurchenko, M., L. M. Shlapatska, and S. P. Sidorenko. (13 Aug, 2012) Figure. Digital image. Experimental Oncology. Morion. Web. 16 Apr. 2105. Retrieved from: http://exp-oncology.com.ua/article/3373/the-multilevel-regulation-of-cd95-signaling-outcome
Tyrosine kinase inhibitors are an important group of target-specific, small molecule enzyme inhibitors that have been studied extensively and represent an expanding group of effective, chemotherapeutic agents. (8) These agents, unlike other cytotoxic agents, can be administered on a daily basis because of their selectivity and favorable safety profile. However, from previously conducted studies, all TKIs appear to be transported by efflux transporters and some of these have also been found to inhibit a few of their own metabolizing enzymes.(13) Pgp, BCRP and MRP1 have been known to facilitate the efflux of numerous conventional anticancer drugs too, including anthracyclines, vinca alkaloids and camptothecins.(25,26,27) Clinical investigations
Lectin belongs to group of structurally diverse proteins and glycoproteins that can bind reversibly to specific carbohydrate residues. After initial mucosal cell binding, lectins can remain on the cell surface or in case of receptor mediated adhesion possibly become internalized via a process of endocytosis. Lectins not only allow targeted specific attachment but also can control the drug delivery of macromolecular pharmaceuticals.