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 …show more content…
have suggested that the overexpression of Pgp and BCRP correlates well with MDR and is to blame for the poor response to chemotherapy.(1-7, 28) Furthermore, several TKIs like imatinib, nilotinib, dasatinib, lapatinib and sunitinib are known substrates or inhibitors of Pgp and BCRP depending on the affinity they have for the transporter and their concentrations.
It has been demonstrated that TKI efflux occurs at low concentrations while inhibition of the transporter prevails at higher concentrations.(22,29,30) Since TKIs can be administered daily; there is also a higher chance for drug-drug interactions. In addition, the potential for drug-drug interaction increases when the substrates of efflux transporters are administered along with agents that inhibit the transporter activity. Plenty of such interactions have been reported previously and this influences therapy efficacy. For example, gefitinib reversed SN38 resistance in BCRP transfected cells by inhibiting the transporter function and increased topotecan intracellular concentrations.(7) Similarly, nilotinib inhibited the transporter function in a Pgp overexpressing tumor and enhanced paclitaxel concentrations synergistically. In …show more content…
the same study, nilotinib also increased the anticancer effects of doxorubicin in a BCRP overexpressing tumor model.(31) In a clinical study, the bioavailability of irinotecan was enhanced when gefitinib was coadministered to pediatric patients with solid tumors.(32) When all of these findings are considered simultaneously and if TKIs are used in combination, it is likely that they will exert additional beneficial anticancer effects by overcoming efflux transporter mediated resistance, acting as chemosensitizers and increasing intracellular concentrations of Pgp and/or BCRP substrates.(4,34) Such synergistic interactions between TKIs have been investigated by a few research groups. For example, Minocha et al. in their in vivo study showed that the coadminstration of erlotinib and pazopanib led to enhanced pazopanib brain concentrations in mice.(17) Weisberg at al. reported synergy between imatinib and nilotinib with imatinib inhibiting the efflux ABC transporters.(33) As far as we know, there are no published studies that investigate the interaction between different TKIs if they are used in combination with dasatinib to find promising, potent chemosensitizers of both, Pgp and BCRP efflux transporter- mediated MDR. We first evaluated the inhibitory effects of 14 TKIs on Pgp-mediated dasatinib transport. According to our results, from the 14 TKIs that were evaluated, 6 of them, axitinib, imatinib, lapatinib, nilotinib, pazopanib and sorafenib, were found to significantly increase the intracellular concentration of dasatinib through the inhibition of Pgp efflux transporters. In an earlier in-vitro study, Hiwase et al. also reported that nilotinib increased the intracellular concentrations of dasatinib through Pgp inhibition in CML cells. (35,42). Based on this published literature and our results, these 6 TKIs seem to have a significant inhibitory effect on Pgp function. Since these TKIs demonstrated potent Pgp inhibition at 50μM, we chose axitinib, imatinib, lapatinib, nilotinib, pazopanib and sorafenib for further concentration dependent studies. Imatinib, nilotinib and pazopanib were found to be potent Pgp inhibitors and they exhibited concentration dependent inhibition of dasatinib efflux (Pgp inhibition). Their IC50 values were found to be 2.42μM, 6.11μM and 8.06μM. Based on this information, imatinib, nilotinib and pazopanib, could be effective chemosensitizers of dasatinib MDR and even help increase BBB penetration since the presence of Pgp and BCRP was shown to affect the uptake of dasatinib in mice.(10) It has also been demonstrated that the brain penetration of gefitinib and erlotinib is limited by Pgp and BCRP mediated active efflux.(37,38) Further in vivo investigations will help warrant our findings. In contrast to these 6 agents, the other 8 compounds demonstrated weaker inhibitory effects on Pgp. Reliable IC50 values could not be established for axitinib, lapatinib and sorafenib and the contribution of these TKIs to Pgp inhibition appears to be low. We also evaluated the modulatory effect of the 14 TKIs on BCRP-mediated dasatinib transport. Our results revealed that 6 TKIs, axitinib, erlotinib, imatinib, nilotinib, pazopanib and regorafenib can inhibit the BCRP transporter to a significant extent at the tested concentration of 50μM. The other 8 TKIs were found to be either moderate or weak inhibitors of BCRP. Further concentration dependent studies were carried out on the MDCK-II-BCRP cells with axitinib, erlotinib, imatinib, nilotinib, pazopanib and regorafenib. Their IC50 values were found to be 6.89μM, 0.94μM, 2.23μM, 2.50μM and 10.41μM respectively. Erlotinib, imatinib and nilotinib appear to be strong, potent inhibitors of BCRP. Axitinib and pazopanib have higher IC50 values and might not be as strong as the other three TKIs. In case of regorafenib, we were not able to find a reliable estimate for the IC50 and it might be a potent inhibitor of BCRP, but our results do not support this. Imatinib, nilotinib and pazopanib were found to be potent inhibitors of both Pgp and BCRP transporters. To our best knowledge, this is the first time that the strong inhibitory potential of pazopanib on Pgp and BCRP transporters is being reported. Dasatinib intracellular concentrations were increased and these agents in combination with dasatinib are likely to lead to additive or synergistic chemotherapeutic effect and increased efficacy plus improved brain penetration of dasatinib. Our cellular uptake studies were also performed using wild type LLC-PK1 and MDCK-II cells.
Both these cell lines are known to express endogenous transporters (39) and results from these studies should be interpreted with caution. When uptake studies were done in LLC-PK1 wild type cells, dasatinib intracellular concentrations were found to be significantly increased in the presence of 50μM pazopanib and regorafenib. LLC-PK1 cells express endogenous BCRP and pazopanib and regorafenib were found to be significant BCRP inhibitors in our earlier uptake study with MDCK-II-BCRP cells. Therefore, it is likely that these endogenous BCRP transporters maybe responsible for the uptake change observed. Further, dasatinib intracellular concentrations significantly decreased in the presence of afatinib, bosutinib, gefitinib, imatinib, lapatinib, ponatinib, sunitinib and vandetanib. LLC-PK1 cells do not express OATP-C uptake transporters.(40) Dasatinib uptake studies in MDCK-II wild type cells revealed a slightly different trend. Among the 14 ingredients screened, 6 of them, namely, axitinib, erlotinib, imatinib, lapatinib, nilotinib and pazopanib exhibited a significant increase in dasatinib intracellular concentrations. MDCK-II cells have very little BCRP expression but have endogenous Pgp expression. Since axitinib, imatinib, lapatinib, nilotinib and pazopanib showed potent Pgp inhibition in the uptake study conducted in LLC-PK1-Pgp cells, the increased dasatinib uptake in MDCK-II wild
type cells can be attributed to that. Erlotinib showed significant Pgp inhibition too, but to a lesser extent and this helps explain the increased dasatinib uptake with erlotinib in the MDCK-WT cells. Regorafenib showed significantly decreased dasatinib uptake in the MDCK-II wild type cell uptake study (p<0.01 Figure 5). Dasatinib uptake is not significantly affected by decreased hOCT-1 expression and Zimmerman et al. established that dasatinib is a substrate of OATP1B3.(20, 41,43) In another study, imatinib, nilotinib, gefitinib and erlotinib were found to be potent inhibitors of MATE1, OCT3, MATE2K and OCT1 respectively.(44) Vandetanib was found to significantly inhibit OATP1B3.(45) Since MDCK-II cells are known to express endogenous OATP uptake transporters(39,40); the inhibition of either OATP transporters or one of the other above mentioned transporters might serve as a likely explanation for the significant decrease in dasatinib uptake that was observed in the LLC-PK1 and MDCK-II wild type uptake studies. In our current study, we used dasatinib as our model TKI. Other TKIs have also been reported to be Pgp and BCRP substrates. In order to confirm the inhibitory activity of the TKIs which were potent efflux transporter inhibitors, further studies will have to be done using other TKIs as substrates. Additionally, further in vivo work using this data will help us scale up the results to animals and eventually to humans. In conclusion, imatinib, nilotinib and pazopanib were found to potent Pgp inhibitors. Axitinib, erlotinib, imatinib, nilotinib and pazopanib were potent BCRP inhibitors. These TKIs increased intracellular dasatinib concentrations and may be effective as chemosensitizers in dasatinib resistant tumors. Hence, they represen
Pharmaceuticals have examined and found to ”work by changing the biological functions of the target cells in the body through chemical agents“ (Doweiko, 2015, p. 16). ”Many people in the past have thought that drugs that
G-protein-linked receptors are protein receptors, located in the plasma membrane of a cell, that work with G-proteins to activate a cell-signaling pathway. These receptors are structured similarly in most organisms, with seven α helices and specific loops for binding sites for signal molecules and G-proteins. When a signal molecule from the extracellular fluid attaches to the signal-binding site it activates the G-protein-linked receptor by changing its shape. When this happens, the G-protein, loosely attached to the cytoplasmic side of the cellular membrane, attaches to its binding side on the receptor protein. The inactive G-protein becomes activated when GDP is displaced by GTP, a molecule similar to ATP. When the signal molecule is released, the G-protein diffuses along the cell membrane and attaches to an inactive enzyme. This newly activated enzyme triggers the cellular response. When the protein detaches itself from the enzyme, it releases a phosphate group turning GTP back into GDP, making the G-protein inactive once again.
The molecular formula is C23H27FN4O2, with a molecular weight of 410.49 (Ereshefsky & Mascarena, 2003). Route of administration is oral. Once the drug passes the esophagus and stomach, it makes its way into the small intestines. There are beds of capillaries within the intestine walls.
Homeostasis is essential to the cell’s survival. The cell membrane is responsible for homeostasis. The membrane has a selective permeability which means what moves in and out of the cell is regulated. Amino acids, sugars, oxygen, sodium, and potassium are examples of substances that enter the cell. Waste products and carbon dioxide are removed from the cell.
...se them to become resistant to Gleevec. These mutations change the shape of bcr-abl to some extent that the treatment will not work on them, such that Gleevec can no longer bind to bcr-abl and activate it; which leads to gleevec resistance within patients with CML. Yet, using another Kinase inhibitor as an alternative to Gleevec which would block the mutated version of bcr-abl that causes resistance with Gleevec could be used to treat the new mutated version of bcr-abl. Such as: dasatinib, nilotinib, bosutinib, or ponatinib. Subsequently, even if the bcr-abl gene is not found in the patients blood, that still doesn't guarantee they are cured for now, so they are recommended to stay on the drug indefinitely. If all fails then patients are told to consider stem cell transplant as a last resort, especially for younger people who have a donor with a matching tissue type.
Altman, Lawrence K. ìShark Substance Found to Limit Tumor Growth.î New York Times 1 May 1996: A15.
Blockbuster drugs are usually a significant therapeutic breakthrough compared to previously available therapies. However greater therapeutic value alone is not enough for cr...
1. Discuss the structure of the plasma membrane and explain the process of active and passive transport through the membrane.
* We would have to leave one end open to fill it up with the different
The Importance of Diffusion to Living Organisms Diffusion is basically the movement of chemical species (ions or molecules) under the influence of concentration difference. The species will move from the high concentration area to the low concentration area till the concentration is consistent in the whole system. Diffusion mostly occurs in gases and liquids as these can move freely. The main features of an efficient diffusion system would be that it has a large surface area, thin membrane and a continuous supply of substances. A large surface area is needed so that high amount of substances can be exchanged at a time while the thin membrane means that the diffusion pathway would be short so that it is more efficient.
Glucose is the primary source of energy for the cells and consequently is necessary for all cellular functions that require energy. Facilitated diffusion plays a significant role in the management of concentrations of glucose, both intracellular and extracellular, providing a balance of glucose in the cells that when poorly utilized upsets the body’s homeostasis.
Chemotherapy drugs are more dangerous than other drugs because of their narrow therapeutic index. What is therapeutic index you ask? It is the ratio between a toxic dose and a therapeutic dose of a drug so any medication error with chemotherapy drugs could be a fatal one. Chemotherapy drugs can be very toxic even at the prescribed therapeutic level recommended by the physician. The findings in this article shows that the patient themselves are the first line of defense in spotting errors in medications they receive because they obs...
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.
Transport Across Plasma Membrane The plasma membrane covers all living cells, enabling the cells’ contents to be held together and controls movement of substances into and out of the cell. Plasma membranes are made of phospholipids, proteins and carbohydrates. The phospholipids are essentially made out of two fatty acid chains and a phosphate-glycerol group. They are arranged in a bilayer with the hydrophilic phosphate head facing outwards and the hydrophobic fatty acid chains facing inwards and to each other in the middle of the bilayer.
Exchange and Transport in Protozoa The exchange of gases between the environment and cells occurs via the process of diffusion. Diffusion depends on: · The amount of surface area available for diffusion. The larger the surface area the greater the rate of diffusion. · The concentration gradient. An organism which respires very quickly will have a much lower concentration of oxygen in the cells and a higher than normal concentration of Carbon Dioxide.