A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R–3327G and anabolic activity on skeletal muscle mass & function in castrated mice

The partial agonist activity of a selective androgen receptor modulator (SARM) in the prostate was demonstrated in orchidectomized rats. In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (a structurally related SARM referred to in other publications and hereafter as S-4) in skeletal muscle, bone, and pituitary of castrated male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 wk. S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were also observed in DHT-treated (3 mg/kg) animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights moire than 2-fold greater than that observed in intact controls, whereas S-4 (3 mg/kg) returned these androgenic organs to only 16 and 17%, respectively, of the control levels. S-4 (3 and 10 mg/kg) and DHT (3 mg/kg) restored castration-induced loss in lean body mass. Furthermore, S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. S-4 (3 and 10 mg/kg) also demonstrated agonist activity in the pituitary and significantly decreased plasma LH and FSH levels in castrated animals in a dose-dependent manner. In summary, the strong anabolic effects of S-4 in skeletal muscle, bone, and pituitary were achieved with minimal pharmacologic effect in the prostate. The tissue-selective pharmacologic activity of SARMs provides obvious advantages over steroidal androgen therapy and demonstrates the promising therapeutic utility that this new class of drugs may hold.

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Enobosarm (GTx-024) Modulates Adult Skeletal Muscle Mass Independently of the Androgen Receptor in the Satellite Cell Lineage

Endocrinology ◽

10.1210/en.2015-1479 ◽

2015 ◽

Vol 156 (12) ◽

pp. 4522-4533 ◽

Cited By ~ 27

Author(s):

Vanessa Dubois ◽

Ioannis Simitsidellis ◽

Michaël R. Laurent ◽

Ferran Jardi ◽

Philippa T. K. Saunders ◽

...

Keyword(s):

Skeletal Muscle ◽

Androgen Receptor ◽

Satellite Cell ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Cell Lineage ◽

Levator Ani ◽

Levator Ani Muscle ◽

Adult Skeletal Muscle ◽

Receptor Modulator

Androgens increase skeletal muscle mass, but their clinical use is hampered by a lack of tissue selectivity and subsequent side effects. Selective androgen receptor modulators elicit muscle-anabolic effects while only sparingly affecting reproductive tissues. The selective androgen receptor modulator, GTx-024 (enobosarm), is being investigated for cancer cachexia, sarcopenia, and muscle wasting diseases. Here we investigate the role of muscle androgen receptor (AR) in the anabolic effect of GTx-024. In mice lacking AR in the satellite cell lineage (satARKO), the weight of the androgen-sensitive levator ani muscle was lower but was decreased further upon orchidectomy. GTx-024 was as effective as DHT in restoring levator ani weights to sham levels. Expression of the muscle-specific, androgen-responsive genes S-adenosylmethionine decarboxylase and myostatin was decreased by orchidectomy and restored by GTx-024 and DHT in control mice, whereas the expression was low and unaffected by androgen status in satARKO. In contrast, insulin-like growth factor 1Ea expression was not different between satARKO and control muscle, decreased upon castration, and was restored by DHT and GTx-024 in both genotypes. These data indicate that GTx-024 does not selectively modulate AR in the satellite cell lineage and that cells outside this lineage remain androgen responsive in satARKO muscle. Indeed, residual AR-positive cells were present in satARKO muscle, coexpressing the fibroblast-lineage marker vimentin. AR positive, muscle-resident fibroblasts could therefore be involved in the indirect effects of androgens on muscle. In conclusion, both DHT and GTx-024 target AR pathways in the satellite cell lineage, but cells outside this lineage also contribute to the anabolic effects of androgens.

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DXA Appendicular Lean Soft Tissue Association with Skeletal Muscle Mass Function

Medicine & Science in Sports & Exercise ◽

10.1249/00005768-200405001-00330 ◽

2004 ◽

Vol 36 (Supplement) ◽

pp. S70

Author(s):

Nana K. Asare ◽

Steven B. Heymsfield ◽

Mary N. Horlick ◽

Alfredo Jones II ◽

Mark Punyanita ◽

...

Keyword(s):

Skeletal Muscle ◽

Soft Tissue ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Mass Function

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Selective Androgen Receptor Modulator S42 Suppresses Prostate Cancer Cell Proliferation

Endocrinology ◽

10.1210/en.2018-00099 ◽

2018 ◽

Vol 159 (4) ◽

pp. 1774-1792 ◽

Cited By ~ 3

Author(s):

Takako Kawanami ◽

Tomoko Tanaka ◽

Yuriko Hamaguchi ◽

Takashi Nomiyama ◽

Hajime Nawata ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Androgen Receptor ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Proliferation ◽

Selective Androgen Receptor Modulator ◽

Receptor Modulator

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Effects of 6 months of abiraterone acetate (AA) on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.222 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 222-222 ◽

Cited By ~ 1

Author(s):

Samuel Craig Brondfield ◽

Vivian K. Weinberg ◽

Kathryn M. Koepfgen ◽

Arturo Molina ◽

Charles J. Ryan ◽

...

Keyword(s):

Prostate Cancer ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Wasting ◽

Cross Sectional Area ◽

Sectional Area ◽

Cross Sectional ◽

Adipose Mass

222 Background: AA, an inhibitor of androgen biosynthesis, has been shown to prolong overall survival in patients with mCRPC who have previously been treated with chemotherapy. Androgen deprivation therapy (ADT) has been shown to result in muscle wasting in prostate cancer pts. The effects of AA on progression of muscle and fat wasting have not been characterized. We evaluated whether 6 months of AA therapy altered total skeletal muscle mass or adipose mass. Methods: 10 sequential pts who responded to AA therapy for at least 6 months and had available computed tomography (CT) scans were retrospectively selected from the phase I-II COU-AA-002 study. CT image analysis was used to quantify change from baseline in total skeletal muscle and adipose tissue after 6 months of AA treatment. Skeletal muscle and adipose tissue cross-sectional area were calculated at the L3 level using Slice-O-Matic software V4.3. Previously published regression models were used to estimate fat-free mass, fat mass and skeletal muscle mass. Paired t-tests were performed to determine the change in measurements. Results: At baseline, 7 of 10 pts were overweight or obese (body mass index [BMI] > 25 kg/m2), and none were underweight. Advanced muscle wasting (sarcopenia, previously defined as the ratio of skeletal muscle cross-sectional area at L3 level to height < 52.4 cm2/m2) was present at baseline and 6 months in 9 of 10 pts. Over 6 months of AA treatment, pts lost an average of 1.9 kg ± 1.9 kg (p = 0.13). Mean changes (kg) (±standard deviation) in total skeletal muscle mass (−0.80 ± 1.71, p = 0.18) and total non-adipose mass (−1.44 ± 3.09, p = 0.17) were not significant. A significant decrease in total adipose mass (−0.61 ± 0.84, p = 0.048) was observed. Conclusions: Sarcopenia is prevalent in pts with mCRPC. AA was not related to significantly worsening sarcopenia or overall weight loss during the first 6 months of treatment; however, this may reflect a relatively short duration of therapy and/or small sample size. A significant loss of adipose tissue was observed, which is unexpected given the known effects of ADT, which increases adipose mass. Evaluation of additional AA treated patients is ongoing.

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Spironolactone: A selective androgen receptor modulator in castration-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.212 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 212-212 ◽

Cited By ~ 2

Author(s):

Philippe Barthelemy ◽

Eva Erdmann ◽

Brigitte Duclos ◽

Jean Pierre Bergerat ◽

Jean-Emmanuel Kurtz ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Abiraterone Acetate ◽

Functional Assay ◽

Castration Resistant Prostate Cancer ◽

Lncap Cells ◽

Selective Androgen Receptor Modulator ◽

Receptor Modulator ◽

Castration Resistant ◽

High Concentrations

212 Background: Spironolactone is an effective drug to treat arterial hypertension as well as fluid retention and hypokalemia. Recently, some data suggested that spironolactone might induce progression in castration-resistant prostate cancer (CRPC) patients treated by abiraterone acetate, a recently approved selective CYP17 inhibitor. Nevertheless, no biological data are available to explain these clinical observations. The purpose of this study was to identify the potential underlying molecular mechanism. Methods: Effect of spironolactone with or without Abiraterone acetate (AA) on androgen receptor (AR) was assessed on LNCaP cells in this study. We performed a yeast-based functional assay with different levels of spironolactone with and without AA. The nuclear localization and activation of androgen receptor (AR) were detected by immunofluorescence and luciferase assays. Results: Results from the yeast-based functional assay show that the wild type androgen receptor is activated by high concentrations of spironolactone in an androgen-depleted environment. Moreover, spironolactone-induced AR transcriptional activity is downregulated by different AR antagonists as well as high concentrations of AA. These results suggest that spironolactone is possibly a potential AR modulator. Luciferase reporter assays showed that AR transcriptional activity in LNCaP cells was upregulated by spironolactone as well. Finally, AR immunoreactivity was almost nuclear in spironolactone-exposed cells. Taken together, these results suggest that spironolactone is a selective androgen receptor modulator. Conclusions: Spironolactone is a selective androgen receptor modulator and should be used with caution in routine practice in patient with metastatic prostate cancer treated by hormonotherapy especially AA.

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Effects of 6 months of abiraterone acetate (AA) on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15137 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15137-e15137

Author(s):

Samuel Craig Brondfield ◽

Vivian K. Weinberg ◽

Kathryn M. Koepfgen ◽

Arturo Molina ◽

Charles J. Ryan ◽

...

Keyword(s):

Prostate Cancer ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Wasting ◽

Cross Sectional Area ◽

Sectional Area ◽

Cross Sectional ◽

Adipose Mass

e15137 Background: AA, an inhibitor of androgen biosynthesis, has been shown to prolong overall survival in patients with mCRPC who have previously been treated with chemotherapy. ADT has been shown to result in muscle wasting in prostate cancer patients. The effects of AA on progression of muscle and fat wasting have not been characterized. We evaluated whether 6 months of AA therapy altered total skeletal muscle mass or adipose mass. Methods: 10 sequential patients who responded to AA therapy for at least 6 months and had available computed tomography (CT) scans were retrospectively selected from the phase I-II COU-AA-002 study. CT image analysis was used to quantify change from baseline in total skeletal muscle and adipose tissue after 6 months of AA treatment. Skeletal muscle and adipose tissue cross-sectional area were calculated at the L3 level using Slice-O-Matic software V4.3. Previously published regression models were used to estimate fat-free mass, fat mass and skeletal muscle mass. Paired t-tests were performed to determine the change in measurements. Results: At baseline, 7 of 10 patients were overweight or obese (body mass index [BMI] > 25 kg/m2), and none were underweight. Advanced muscle wasting (sarcopenia, previously defined as the ratio of skeletal muscle cross-sectional area at L3 level to height < 52.4 cm2/m2) was present at baseline and 6 months in 9 of 10 pts. Over 6 months of AA treatment, patients lost an average of 1.9 kg ± 3.6 kg (p = 0.13). Mean changes (kg) (±standard deviation) in total skeletal muscle mass (-0.80 ± 1.71, p = 0.18) and total non-adipose mass (-1.44 ± 3.09, p = 0.17) were not significant. A significant decrease in total adipose mass (-0.61 ± 0.84, p = 0.048) was observed. Conclusions: Sarcopenia is prevalent in patients with mCRPC. AA was not related to significantly worsening sarcopenia or overall weight loss during the first 6 months of treatment; however, this may reflect a relatively short duration of therapy and/or small sample size. A significant loss of adipose tissue was observed, which is unexpected given the known effects of ADT, which increases adipose mass. Evaluation of additional AA treated patients is ongoing.

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Proteome-wide muscle protein fractional synthesis rates predict muscle mass gain in response to a selective androgen receptor modulator in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00257.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. E405-E417 ◽

Cited By ~ 12

Author(s):

Mahalakshmi Shankaran ◽

Todd W. Shearer ◽

Stephen A. Stimpson ◽

Scott M. Turner ◽

Chelsea King ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Androgen Receptor ◽

Muscle Mass ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Synthesis Rate ◽

Muscle Proteins ◽

Receptor Modulator ◽

Fractional Synthesis

Biomarkers of muscle protein synthesis rate could provide early data demonstrating anabolic efficacy for treating muscle-wasting conditions. Androgenic therapies have been shown to increase muscle mass primarily by increasing the rate of muscle protein synthesis. We hypothesized that the synthesis rate of large numbers of individual muscle proteins could serve as early response biomarkers and potentially treatment-specific signaling for predicting the effect of anabolic treatments on muscle mass. Utilizing selective androgen receptor modulator (SARM) treatment in the ovariectomized (OVX) rat, we applied an unbiased, dynamic proteomics approach to measure the fractional synthesis rates (FSR) of 167–201 individual skeletal muscle proteins in triceps, EDL, and soleus. OVX rats treated with a SARM molecule (GSK212A at 0.1, 0.3, or 1 mg/kg) for 10 or 28 days showed significant, dose-related increases in body weight, lean body mass, and individual triceps but not EDL or soleus weights. Thirty-four out of the 94 proteins measured from the triceps of all rats exhibited a significant, dose-related increase in FSR after 10 days of SARM treatment. For several cytoplasmic proteins, including carbonic anhydrase 3, creatine kinase M-type (CK-M), pyruvate kinase, and aldolase-A, a change in 10-day FSR was strongly correlated ( r2 = 0.90–0.99) to the 28-day change in lean body mass and triceps weight gains, suggesting a noninvasive measurement of SARM effects. In summary, FSR of multiple muscle proteins measured by dynamics of moderate- to high-abundance proteins provides early biomarkers of the anabolic response of skeletal muscle to SARM.

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Dietary wild bitter gourd displays selective androgen receptor modulator like activity and improves the muscle decline of orchidectomized mice

Food & Function ◽

10.1039/c8fo01777h ◽

2019 ◽

Vol 10 (1) ◽

pp. 125-139 ◽

Cited By ~ 1

Author(s):

Chih-Ling Wang ◽

Hsiu-Ni Kung ◽

Ching-Ho Wu ◽

Ching-jang Huang

Keyword(s):

Skeletal Muscle ◽

Androgen Receptor ◽

Muscle Function ◽

Bitter Gourd ◽

Selective Androgen Receptor Modulator ◽

Skeletal Muscle Function ◽

Receptor Modulator ◽

Selective Androgen Receptor Modulators ◽

Receptor Modulators

Wild bitter gourd, like selective androgen receptor modulators (SARMs), restored the mass of androgen responsive muscles but not prostate and might improve skeletal muscle function in orchidectomized mice.

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