Group:SMART:P-glycoprotein: Why Cancer Drugs Fail: Difference between revisions

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Recently the X-ray structure of P-gp was resolved (Aller et al, 2009). We have built a 3-D physical model based on this X-ray structure which highlights the hydrophobic and hydrophilic regions of the protein, nucleotide binding domains, and active site residues that are important for verapamil, a common heart medication, binding. As it has not yet been possible to identify whether a drug is or is not a substrate of P-glycoprotein, this 3-D model may lend insight into this prediction.

==So... What is P-gp?==

P-glycoprotein (P-gp) is an active transporter in the cell membrane of liver, blood-brain barrier and small intestine cells. P-gp’s role is to guard the body against foreign and harmful substances by transporting “toxins” out of the cells. P-gp is one of the body’s best line of defense against harmful toxins; it prevents damage to cells. Normally, P-gp would be considered a protein that is beneficial for the protection of our body, but in the case with pharmaceuticals, it is considered an obstacle. Drug companies have produced drugs that can possibly treat cancer; however, P-gp recognizes these drugs as harmful or toxic to the body. As a result, P-gp would eject the drug before it can take its desired effects on the body. Nevertheless, P-gp is crucial to the human body. For example, P-gp in liver cells help remove toxins in blood cells. The P-gp in blood-brain barrier cells protect the brain from dangerous substances in the blood while the P-gp in the small intestine help remove toxins from digested food.

==Our Model==

[[Image:Pgp Movement Diagram.png|250px|left]]

In our model of P-glycoprotein, the hydrophilic regions are highlighted in magenta, the hydrophobic regions are highlighted in violet, the active site residues for the drug Verapamil(-) is highlighted in green, and the Nucleotide Binding Domains or NBDs are highlighted in yellow. Since P-glycoprotein is a dimer, a molecule consisting of two similar subunits, only half of the dimer (or one of two subunits) is shown in our model.

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==Medical Implications==

[[Image:Medical Implications.jpg|250px|left]]

The function of P-glycoprotein (P-gp) provides the tumor cells of cancer patients with resistance to a variety of anti-cancer drugs such as Vincristine because it pumps out any drugs that enter the tumor cells. Due to such activities, the dosage of drugs that enter the cell is inadequate in fulfilling its duty and taking its desired effect.

Depending on the dosage, Verapamil can be a P-gp inhibitor. For example, Verapamil can help anti-cancer drugs enter targeted cells by “distracting” P-gp; thus, decreasing P-gp’s activity on anti-cancer drugs. When Verapamil is taken with Vincristine, an anti-drug, the effects are beneficial to the patient because P-gp would be focused on transporting Verapamil out, allowing for Vincristine to enter the cell. This offers hope and promise in increasing the effectiveness of chemotherapy in cancer patient though the use of anti-cancer drugs with P-glycoprotein inhibitors in does determined for each individual.

Verapamil, a P-gp inhibitor, helps anti-cancer drugs go into cells by “distracting” P-gp; thus, decreasing P-gp’s activity on anti-cancer drugs. For example, when an anticancer drug such as, Vincristine, is taken with Verapamil, the effects are beneficial to the patient because P-gp is focused on taking Verapamil so that Vincristine can get into the cell. This offers promise in increasing the effectiveness of chemotherapy in patients with cancer through the combined use of anticancer drugs with P-glycoprotein inhibitors (in doses determined for each individual).

~~<applet load~~=~~'3g60' size~~=~~'300' frame~~=~~'true' align~~=~~'right' caption='Insert caption here'~~ />

==Additional Resources==

For additional information, see: [[Cancer]]

@@ Line 22: / Line 22: @@
 Recently the X-ray structure of P-gp was resolved (Aller et al, 2009). We have built a 3-D physical model based on this X-ray structure which highlights the hydrophobic and hydrophilic regions of the protein, nucleotide binding domains, and active site residues that are important for verapamil, a common heart medication, binding. As it has not yet been possible to identify whether a drug is or is not a substrate of P-glycoprotein, this 3-D model may lend insight into this prediction.
+==So... What <i>is</i> P-gp?==
+P-glycoprotein (P-gp) is an active transporter in the cell membrane of liver, blood-brain barrier and small intestine cells. P-gp’s role is to guard the body against foreign and harmful substances by transporting “toxins” out of the cells. P-gp is one of the body’s best line of defense against harmful toxins; it prevents damage to cells. Normally, P-gp would be considered a protein that is beneficial for the protection of our body, but in the case with pharmaceuticals, it is considered an obstacle. Drug companies have produced drugs that can possibly treat cancer; however, P-gp recognizes these drugs as harmful or toxic to the body. As a result, P-gp would eject the drug before it can take its desired effects on the body. Nevertheless, P-gp is crucial to the human body. For example, P-gp in liver cells help remove toxins in blood cells. The P-gp in blood-brain barrier cells protect the brain from dangerous substances in the blood while the P-gp in the small intestine help remove toxins from digested food.
 ==Our Model==
+[[Image:Pgp Movement Diagram.png|250px|left]]
 In our model of P-glycoprotein, the hydrophilic regions are highlighted in <font color=magenta><b>magenta</b></font>, the hydrophobic regions are highlighted in <font color=#9933FF><b>violet</b></font>, the active site residues for the drug Verapamil(-) is highlighted in <font color=lime><b>green</b></font>, and the Nucleotide Binding Domains or NBDs are highlighted in <font color=gold><b>yellow</b></font>. Since P-glycoprotein is a dimer, a molecule consisting of two similar subunits, only half of the dimer (or one of two subunits) is shown in our model.
@@ Line 35: / Line 39: @@
+==Medical Implications==
+[[Image:Medical Implications.jpg|250px|left]]
+The function of P-glycoprotein (P-gp) provides the tumor cells of cancer patients with resistance to a variety of anti-cancer drugs such as Vincristine because it pumps out any drugs that enter the tumor cells. Due to such activities, the dosage of drugs that enter the cell is inadequate in fulfilling its duty and taking its desired effect.
+Depending on the dosage, Verapamil can be a P-gp inhibitor. For example, Verapamil can help anti-cancer drugs enter targeted cells by “distracting” P-gp; thus, decreasing P-gp’s activity on anti-cancer drugs. When Verapamil is taken with Vincristine, an anti-drug, the effects are beneficial to the patient because P-gp would be focused on transporting Verapamil out, allowing for Vincristine to enter the cell. This offers hope and promise in increasing the effectiveness of chemotherapy in cancer patient though the use of anti-cancer drugs with P-glycoprotein inhibitors in does determined for each individual.
+Verapamil, a P-gp inhibitor, helps anti-cancer drugs go into cells by “distracting” P-gp; thus, decreasing P-gp’s activity on anti-cancer drugs. For example, when an anticancer drug such as, Vincristine, is taken with Verapamil, the effects are beneficial to the patient because P-gp is focused on taking Verapamil so that Vincristine can get into the  cell. This offers promise in increasing the effectiveness of chemotherapy in patients with cancer through the combined use of anticancer drugs with P-glycoprotein inhibitors (in doses determined for each individual).
-<applet load='3g60' size='300' frame='true' align='right' caption='Insert caption here' />
+==Additional Resources==
+For additional information, see: [[Cancer]]
+<br />