Erectile Dysfunction (ED) Drugs And Pulmonary Arterial Hypertension (PAH) Medications May Cause Increased Rate Of Melanoma Metastasis
(Posted by Tom Lamb at DrugInjuryWatch.com)
To start, we get our background facts and some commentary from "Hard Times for Oncogenic BRAF-Expressing Melanoma Cells", a Preview piece in the January 2011 edition of the Cancer Cell medical journal.
- [Malignant cutaneous melanoma] progression occurs in around 20% of cases to an aggressive, metastasizing form of the disease with extremely poor patient survival rates
- Nearly half of all melanomas carry an activating mutation in BRAF
- Recently, Marais and colleagues (Arozarena et al., 2011) have provided an extremely exciting and novel insight into the critical issue of melanoma cell invasiveness, discovering that it can be elicited by the downregulation of PDE5A
- Active-site directed selective inhibitors of this enzyme are used acutely for the treatment of penile erectile dysfunction (PED) and infantile hypertension
- This elegant study thus provides an important insight into the mechanism whereby oncogenic B-RAF promotes invasiveness in melanoma cells through a mechanism that pivotally involves PDE5A downregulation and elevation of cGMP levels
The study by Marais and colleagues mentioned in those third and fifth points, above, is the subject of this article, "Oncogenic BRAF Induces Melanoma Cell Invasion by Downregulating the cGMP-Specific Phosphodiesterase PDE5A", which appeared in that same edition of the Cancer Cell medical journal.
For an overview, we get this text from the article's Significance section:
The protein kinase BRAF is activated by somatic gain-of-function mutations in about 44% of human melanomas. This results in ERK pathway hyper-activation, and we show that this leads to downregulation of PDE5A, a cGMP-selective phosphodiesterase. PDE5A is the target of drugs such as [Viarga and Revatio (sildenafil)], [Cialis and Adcirca (tadalafil)], and [Levitra and Staxyn (vardenafil)], which are used to treat erectile dysfunction and pulmonary arterial hypertension. PDE5A downregulation by V600EBRAF induces melanoma cell invasion in vitro and in vivo and increased long-term colonization of the lungs by melanoma cells. PDE5A inhibition by sildenafil induces invasion in vitro but does not increase lung colonization. Our study establishes a link between PDE5A, cGMP, and Ca2+ metabolism, and the regulation of invasion by oncogenic BRAF in melanoma cells.
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In more detail, from the Discussion part of this 2011 Cancer Cell article:
Thus, we conclude that PDE5A is not a therapeutic target in melanoma, and our data even raise the possibility that PDE5A drugs could promote melanoma metastasis....
However, we do not perceive this to be a problem. There are no reports linking these drugs [i.e., Viagra and Revatio (sildenafil), Cialis and Adcirca (tadalafil), Levitra and Staxyn (vardenafil), and Stendra (avanafil] to increased risk of melanoma metastasis, and we found that sildenafil did not increase mouse lung colonization by melanoma cells. Furthermore, PDE5A drugs are generally used as needed rather than persistently and are generally cleared rapidly (T1/2 ∼2 hr) because their effects must be short lived.
Therefore, our data should be interpreted with care, and we do not immediately suggest that PDE5A inhibitors will drive melanoma metastasis. However, we caution that with the ever-widening clinical use of these drugs, it is not possible to discount this risk completely.
While Marais and his colleagues in this article did not associate Cialis, Levitra, Viagra, etc. with a higher rate of invasive melanoma, their medical study left the door open for there being a link between PDE5A inhibitor drugs and an increased risk of melanoma metastasis.
Then, a few years later, comes this rather high profile 2014 medical journal article about Viagra, "Sildenafil Use and Increased Risk of Incident Melanoma in US Men: A Prospective Cohort Study", published by JAMA Internal Medicine.
So, at the very least, the link between Cialis, Levitra, Viagra, etc. with a higher rate of invasive melanoma seems to remain possible, as we discussed in this November 2014 post, "The Link Between Popular Erectile Dysfunction (ED) Drug Viagra And Melanoma Has A Potential Molecular Basis According To Medical Expert Who Reviewed Recent Study".
We are currently investigating cases of melanoma in men who used Viagra, Cialis, Levitra, Staxyn, or Stendra as well as men and women who used Revatio or Adcirca, as possible drug injury lawsuits against the responsible pharmaceutical companies.
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