Bicalutamide Mechanism Of Action Prostate Cancer

Slow Growth Free Energy Perturbation

Although FEP theory has been used for calculation of the free energy of ligand binding, for this purpose it is only valid for small perturbations of ligand structure . Instead we have exploited it here to reduce the bias in ligand placement. In this protocol the ligand is grown slowly in situ . Our objective, rather that determining binding free energy, is to allow time for the protein structure to adapt to the new ligand gently rather than creating a bias by forcing the insertion of the ligand into the 1T63 structure. This is accomplished according to the equation

The FEP stage was performed with a timestep of 1fs and the nonbonded interactions between Bcu and AR were turned on continuously over a 1ns interval by scaling lambda linearly, from 0.0 to 1.0, while the temperature was linearly annealed from 0.1 K to 306 K for the first 0.5 ns, then remaining constant at 306 K for the final 0.5ns of the FEP stage. Following this the simulation was continued another 5ns.

What Should I Know About Storage And Disposal Of This Medication

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture .

It is important to keep all medication out of sight and reach of children as many containers are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location â one that is up and away and out of their sight and reach.

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA’s Safe Disposal of Medicines website for more information if you do not have access to a take-back program.

Quantification By Liquid Chromatographic /tandem Mass Spectrometric Analysis

Preparation of calibration curve

Authentic testosterone and Bic at 1mg each, were exactly weighed and dissolved in 1mL acetonitrile to make stock solutions . The testosterone stock solution was diluted with acetonitrile to concentrations 0.0125, 0.025, 0.05, 0.10, and 0.20 ppm. These diluted standard solutions were used for calibration. Acetonitrile was used as the blank. The stock solution of Bic was prepared by dissolving 1mg of Bic in 1mL of acetonitrile to make the stock solution with a concentration of 1mg/mL. This was diluted with acetonitrile to concentrations of 3.125, 6.25, 12.5, and 25g/mL, to establish the calibration curve.

Preparation of samples from culture media

Sample media were extracted with acetonitrile at a volume ratio of 1:1) and vortexed for 5min. Sample tubes were agitated on a shaker with the bottom of the tubes immersed in an ice bath for 10min, then centrifuged at 4°C, and 15000 × g for 10min. The extraction was repeated three times, with 1mL of fresh acetonitrile being replaced each time. The supernatants were collected in a 2-mL fresh tubes and stored at 20°C. One to two days prior to being subjected to the LC/MS/MS analysis, the refrigerated samples were removed and lyophilized. Desiccated samples were redissolved in fresh acetonitrile.

LC/MS/MS analysis

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Are The Intrinsic And Er Stress Pathways Involved In The Process Of Renal Damage

Suspecting the possibility that the intrinsic pathway might be involved in Bic-induced RF,, we examined expressions of apoptotic and antiapoptotic proteins, and ER stress-related calpain-1 and caspase-12. Bic at a dose 15M seemed to have slightly upregulated the Bcl-2 and Bax protein . As a consequence, the Bax/Bcl-2 ratio remained unchanged . On the other hand, calpain-1, caspase-12 and cleaved caspase-12 proteins were entirely unaffected , implying that they obviously have no involvement in the intrinsic and ER stress pathways.

Figure 6

Effect of bicalutamide on expression of proteins related with the intrinsic and ER stress pathways. The intrinsic pathway related proteins Bcl-2 and Bax. The ERassociated calpain-1 and caspase-12 proteins. Western blots were performed in triplicate and quantified . LG: low glucose 5.5mM E: Etoptoside 2M.

Financial And Insurance Assistance

If you need financial support to pay for Casodex, help is available.

Medicine Assistance Tool lists programs that may help lower the cost of Casodex. For more information and to find out if youre eligible for support, visit the program website.

You should take Casodex according to your doctors or healthcare providers instructions.

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Side Effects Of Bicalutamide

• Bicalutamide shows typical side effects of antiandrogens: gynecomastia, hot flushes, decreased libido, decreased erectile function. Sexual side effects are less pronounced than with LHRH treatment.
• Abdominal pain, diarrhea or nausea , rarely vomiting.
• Increased liver enzymes or jaundice.
• Fluid retention, cardiac decompensation
• Anemia , rarely leukopenia, thrombocytopenia
• Allergic reactions

Treatment To Lower Androgen Levels From Other Parts Of The Body

LHRH agonists and antagonists can stop the testicles from making androgens, but cells in other parts of the body, such as the adrenal glands, and prostate cancer cells themselves, can still make male hormones, which can fuel cancer growth. Some drugs can block the formation of androgens made by these cells.

Abiraterone blocks an enzyme called CYP17, which helps stop these cells from making androgens.

Abiraterone can be used in men with advanced prostate cancer that is either:

• Castration-resistant

This drug is taken as pills every day. It doesnt stop the testicles from making testosterone, so men who havent had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, prednisone needs to be taken during treatment as well to avoid certain side effects.

Ketoconazole , first used for treating fungal infections, also blocks production of androgens made in the adrenal glands, much like abiraterone. It’s most often used to treat men just diagnosed with advanced prostate cancer who have a lot of cancer in the body, as it offers a quick way to lower testosterone levels. It can also be tried if other forms of hormone therapy are no longer working.

Ketoconazole also can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid .

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Medical And Dental Treatment

If you need medical treatment for any reason other than cancer, always tell the doctors and nurses you are having cancer treatment. Give them the contact details for your cancer doctor so they can ask for advice.

If you think you need dental treatment, talk to your cancer doctor or nurse. Always tell your dentist you are having cancer treatment.

Functional Analysis Of Altered Protein

Bioinformatics analysis of the 1.8-fold differentially expressed proteins was performed using the Kyoto Encyclopedia of Gene and Genome enrichment analysis program. The apoptosis pathway was chosen in the KEGG category. Functional analysis of the 1.8-fold differentially expressed proteins was conducted using Metacore GeneGo software.

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Lc/ms/ms Analysis Of Testosterone In Culture Medium

Figure shows the LC/MS/MS data obtained from different drug treatments. No trace of testosterone was detected in the Bic control . Attractively, when testosterone was co-treated with Bic , the overall consumption rate of testosterone was found to be retarded by the coexisting Bic. For free testosterone at 500, 300, and 100nM, overall consumption rates were 4.175, 2.982, and 0.785g/mL-h, respectively. When testosterone was co-treated with Bic , corresponding values changed to 3.300, 1.773, and 0.493g/mL-h, respectively, obviously implying a prominent suppressive effect exhibited by Bic against the overall consumption rate of coexisting testosterone . It is suggested that such competition might have occurred on the AR or the membrane transport gate.

Figure 2

LC/MS/MS analysis of testosterone. The standard curve of testosterone. The standard curve of bicalutamide. The timedependent change of extracellular concentration of testosterone.

Force Field Ligand Charges And Torsional Barriers

Simulations were carried out with the OPLS all-atom potential for AR, as implemented in GROMACS . Although potentials for proteins have been well characterized for some years now , this is not the case for arbitrary heterocyclic ligands such as Bcu. Fortunately OPLS had bond stretching and angle bending parameters for the functional groups found in DHT and S1. QM calculations of the more critical rotational barriers of each ligand were carried out and torsion parameters generated to fit these barriers were used. Partial atomic charges on the ligand were determined by QM. These calculations were performed using DFT at the 631G** level with the Jaguar package .

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Protein Extraction And Sample Preparation And Tryptic Digestion

The cellular protein concentration was assessed using the Bradford assay . LNCaP and RWPE-1 cell protein samples were reduced using 5mM Trisphosphine for 30 min at 37°C. The samples were alkylated by treating them with 15 mM iodoacetamide and then they were left for 1 h at 25°C rotated at 300 r/min in the dark. The samples were then treated with mass-spectrometry grade Trypsin Gold overnight at 37°C. The chemical reagent was removed using C18 cartridges .

If I Have Diabetes Can I Take Casodex

You may be able to, but it depends on how well your diabetes is managed. Casodex has to be taken with a type of drug called an LHRH analog such as leuprolide acetate or goserelin acetate . These drugs can cause high blood sugar levels, which can make your blood sugar harder to manage.

You might need to check your blood sugar more often while taking Casodex. If your blood sugar gets too high, your doctor may increase your dosage of diabetes medication. Or you might need extra medications to manage your blood sugar levels.

If you have diabetes and want to take Casodex, talk with your doctor about the risks and benefits.

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Casodex For Metastatic Prostate Cancer

Casodex is approved to treat stage D2 metastatic prostate cancer. This is a form of advanced prostate cancer . Metastatic means the cancer has spread to other parts of the body, such as the pelvis, spine, ribs, or other bones.

Casodex is approved for use with a type of drug called a luteinizing hormone-releasing hormone analog. Both Casodex and LHRH analogs are hormone therapies for prostate cancer. They reduce the effect of the male hormone testosterone on the cancer cells. Testosterone stimulates prostate cancer cells to grow and multiply.

Casodex is a type of drug called an anti-androgen. It blocks testosterone from attaching to prostate cancer cells. LHRH analogs include drugs such as leuprolide acetate and goserelin acetate .

These lower the amount of testosterone that your body makes.

Taking Casodex with an LHRH analog helps slow down or stop the growth of prostate cancer cells.

Bicalutamide 50 Mg Daily In Combination With An Lhrh

In a multi-center, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive Bicalutamide 50 mg once daily or flutamide 250 mg three times a day, each in combination with LHRH analogs .

In an analysis conducted after a median follow-up of 160 weeks was reached, 213 patients treated with Bicalutamide-LHRH analog therapy and 235 patients treated with flutamide-LHRH analog therapy had died. There was no significant difference in survival between treatment groups . The hazard ratio for time to death was 0.87 .

Figure 1 – The Kaplan-Meier probability of death for both antiandrogen treatment groups.

There was no significant difference in time to objective tumor progression between treatment groups . Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of Bicalutamide plus LHRH analog to that of flutamide plus LHRH analog was 0.93 .

Figure 2 – Kaplan-Meier curve for time to progression for both antiandrogen treatment groups.

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Do Older Adults Have More Side Effects From Casodex Than Younger People Have

Its not currently known whether younger people have fewer side effects from Casodex than older adults.

Casodex is only approved to treat prostate cancer, which is a disease that typically affects older men. The American Cancer Society states that the majority of prostate cancer cases occur in men ages 65 years and older. This cancer is rare in men younger than 40 years old. Studies of Casodex use for prostate cancer did not investigate whether age affects how often side effects occur.

Will I Have Withdrawal Symptoms If I Stop Taking Casodex

Withdrawal symptoms are negative side effects that can sometimes happen if you stop taking a drug that your body has come to depend on. Stopping Casodex wont cause withdrawal symptoms.

However, in certain situations your doctor might ask you to stop taking Casodex in order to cause an effect called anti-androgen withdrawal. In this case, stopping Casodex actually improves your prostate cancer, rather than causing withdrawal symptoms.

This treatment approach is not right for everyone. If your doctor thinks Casodex has stopped working for you, talk with them about whether stopping treatment could benefit you.

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Bic Induces Late Apoptosis Of Rmc Cells

When viewed with combined Annexin V and 7-AAD staining, late apoptosis was seen to have occurred after treatment with Bic . The apoptotic population increased in a dose- and time-dependent manner. After 24h of treatment, the late apoptotic population had increased from 15.75% in the control to 26.03% and 32.36% at 30 and 60M, respectively. In contrast, after being treated for 48h, the corresponding values increased from 24.26% for the control to 53.36% and 58.95%, respectively, while no significant change was seen for early apoptosis , apparently supporting the occurrence of late apoptosis. Bic was implicated as an underlying cause of cancer cell apoptosis,. This is believed to be the first report about late apoptosis elicited by Bic in mesangial cells. On the other hand, Bic showed no apparent suppressive effect on the viability of NRK52E cells . We wondered could such a phenomenon as apoptosis be relevantly associated with an alternate cell protective effective that has always been called autophagy? Results seemed to make this unlikely, because that was no trace of LC3-phosphatidylethanolamine conjugate-II detected at 48h . Contrasting this phenomenon associated with NRK52E cells, Bic seemed to play a role of mainly inducing apoptosis of RMC cells. Speculating that such an apoptotic effect might be associated with the caspase signaling pathway, we performed the following study.

Figure 4

About Metastatic Prostate Cancer And Testosterone

Stage D2 metastatic prostate cancer is a form of advanced prostate cancer that has spread to other parts of the body. This usually includes the pelvis, hips, ribs, or other bones. The cancer spreads when prostate cancer cells travel in the blood or lymphatic system to a different part of the body. The cancer cells in the new site are the same type of cells as those in the prostate gland.

The male hormone testosterone stimulates prostate cancer cells to grow and multiply, wherever they are in your body. It does this by attaching to specific sites called receptors found on the surface of the cancer cells.

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Rmc Cell Cycle Populations Were Dose

Taking the DNA content and intensity of the fluorescence as a measure of the cell population in each cell cycle phase , we found that subG1 and G0/G1 apoptosis of RMC cells occurred in dose- and time-dependent manners . The subG1 population markedly increased from 7.4% to 24.26% within the first 24h and progressed to 55.83% when treated with 60M Bic for 48h . At the same time, the S phase population was found to have drastically declined in a dose- and time-dependent manner , implying a decrease in the cell population after DNA replication had finished. Such an outcome could have been caused by a dramatic disruption of telomeric complexes by Bic therapy, as cited elsewhere in the literature,.

Figure 3

The cell cycle analysis of RMC cell line affected by bicalutamide treatment. Histogram for flowcytometric analysis. Quantification of cell populations in 24h. Quantification of cell populations in 48h. Experiment was performed in triplicate

The literature also indicates that Bic-induced cytotoxic and cytostatic effects in androgen-positive PCa LNCaP cells could be associated with a marked G1 phase arrest and S phase depression. Consistent with this, the same mechanism applied similarly to RMC cells .

Increased Migratory Activity Was Enhanced By Bic Therapy

As is well cited, renal mesangial cells and fibroblasts are crucially involved in many progressive renal diseases. Mesangial cell migration through the mesangial matrix and into the pericapillary space in response to PDGF is a feature of a number of renal diseases,. PDGF signaling triggers stromal recruitment and may be involved in the epithelial-to-mesenchymal transition , thereby affecting fibrogenesis and metastasis.

We found that Bic did not show a proliferative effect but only increased cell migration , a result inconsistent with those of Boor et al. and Andrae et al.. Results implied that the mechanism of action regarding PDGF expression was biased by Bic therapy. At this point, we also examined the total collagen content and found that the collagen content was stimulated by Bic in a dose-dependent manner, increasing from 4.02±0.15 to 5.32±0.15, 5.19±0.23, and 6.22±0.25g at Bic doses of 15, 30, and 60M, respectively .

Figure 8

In reality, fibrosis occurring in different organs is contributed to by various sources and different phenotypes of myofibroblasts. Consequently, a better knowledge of the molecular mechanisms associated with the appearance of differentiated myofibroblasts in each pathological status could provide much help in understanding fibrogenic development and more importantly, in planning strategies aimed at its prevention and therapy.

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