New paper below [1].
Why read further? Clorgyline [2] is an antidepressant & may have a role to play in advanced PCa.
{For those who want to skip the papers, see link [4].}
Clorgyline is an inhibitor of MAOA (monoamine oxidase A), a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine.
The story starts more than a dozen years back, but inn 2010, Donna Peehl et al (Stanford) put out a paper: "Targeting monoamine oxidase A in advanced prostate cancer" [3].
"MAOA has been widely studied in the context of neurological disorders such as depression and Parkinson’s disease (Youdim et al. 2006). MAOA is also expressed in non-neuronal tissues, but its biological functions in these tissues are unknown. Recently, MAOA was found to be one of the most highly differentially overexpressed genes at the transcript level in high grade (Gleason grades 4 and 5), poorly differentiated primary PCa compared to low grade (Gleason grade 3), well-differentiated PCa, suggesting a role in the progression and/or aggressiveness of high-grade cancer (True et al. 2006)."
The link [3] below is full text & the Discussion is worth reading, for those so inclined. But here is a small quote:
"... we have shown that clorgyline exerts anti-oncogenic and pro-differentiation effects in a model of advanced PCa, and decreases the proliferative ability of PCa both in vitro and in vivo. The ability of clorgyline to counteract oncogenic pathways and promote differentiation suggests that MAOA inhibitors, which are already used in clinical practice for treating neurological disorders, could be therapeutic options for advanced stages of PCa."
PCa bone mets tend to be osteoblastic, rather than osteoclastic, meaning that the net effect is an increase in bone density, rather than osteolysis. However, "the MAOA enzyme triggers three proteins that enhance the function of the destructive osteoclasts." [4]
from the new paper:
{"Bone metastases consist morphologically of aberrant osteolytic and osteoblastic components (Logothetis and Lin, 2005). PCa bone metastases are most often radiographically characterized as osteoblastic, but histologic evidence reveals a heterogeneous mixture of osteolytic and osteoblastic lesions (Berruti et al., 1996, Percival et al., 1987). The osteoblastic features are well established, and a growing body of evidence shows the fundamental osteolytic component of PCa skeletal metastases (Keller and Brown, 2004, Sottnik and Keller, 2013). The bone resorption step preceding bone formation may be a prerequisite for tumor cell homing to bone and the nourishing of tumor growth by pro-tumorigenic changes in the bone microenvironment (Yonou et al., 2004). Bone resorption is also needed for subsequent bone formation, since osteoblastic metastases are seen to form on trabecular bone at the sites of previous osteoclastic resorption (Carlin and Andriole, 2000, Charhon et al., 1983). This cascade of events suggests that an osteolysis-initiated overall increase in bone turnover and bone remodeling, coupling both osteoclastic and osteoblastic activities, drives osteoblastic PCa bone metastasis (Ibrahim et al., 2010, Keller and Brown, 2004, Sottnik and Keller, 2013)."}
from the discussion:
"Our findings identify the initiation of PCa bone metastasis via an MAOA/Shh-induced osteolytic reaction in the tumor-bone interface, with active participation of osteoblasts, as evidenced by a positive relationship between tumor MAOA expression and osteoblast differentiation and mineralization, dependent on paracrine Shh signaling. The coupling of bone resorption and new bone formation mediated by MAOA/Shh signaling suggests dual roles of MAOA directing PCa cell interactions with osteoclasts and osteoblasts to enhance overall bone turnover and bone remodeling."
"The small-molecule inhibitor clorgyline, which inhibits MAOA enzymatic activity, showed promise in xenograft mouse models, disrupting the Shh-IL6-RANKL signaling network in bone stromal cells. The prevalent upregulation of MAOA in PCa bone and visceral metastases provides a rationale for using MAOA inhibitors to treat PCa metastasis. MAOA inhibitors are used clinically as antidepressants (Shih et al., 1999), and their effects on tumor growth, progression, and metastasis are still under investigation. The effectiveness of MAOA inhibitors for impeding PCa growth has been documented in tumor xenograft models (Flamand et al., 2010, Wu et al., 2014). Our observation that MAOA inhibitors suppressed EMT in tumor xenografts suggests their use for treating metastasis (Wu et al., 2014). In this study MAOA inhibitor treatment effectively restricted PCa metastasis and prolonged mouse survival. However, MAOA inhibitors were reported to promote EMT in breast cancer cells (Satram-Maharaj et al., 2014). These controversial results suggest that the role of MAOA-associated signaling networks during cancer progression may be context dependent."
...
"Although not a major emphasis in this study, we demonstrated that MAOA enhances PCa visceral metastasis in a cell-context-dependent manner. Hence, MAOA upregulation and promotion of metastasis is associated with most sites of PCa metastasis rather than being bone specific."
-Patrick
[1] cell.com/cancer-cell/fullte...
[2] en.wikipedia.org/wiki/Clorg...
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