Minocycline (MC) is a PAK1/MLK-inhibitor: Useful for therapy of brain tumors such NF

A brief review in “Brain Tumors” issue:

Is an old antibiotic “Minocycline” useful for NF therapy? 

Hiroshi Maruta, PAK Research Center, Melbourne, Australia.

ABSTRACT:

So far no effective FDA-approved drug useful for NF (neurofibromatosis) therapy is available on the market.  However, there emerged a good possibility that an old antibiotic called “Minocycline” (MC) could be used (prescribed) for NF therapy at least on a so-called “compassionate” ground. Why?  MC is a tetracyclin derivative, and has been used for therapy of a variety of infectious diseases (including cerebral malaria) as well as thrombosis during last 4 decades without any serious side effect. Besides the generic drug MC is far less expensive than Gleevec, the ABL/PDGFR/KIT-inhibitor, approved by FDA only for therapy of rare cancers such as CML and GIST. Recently a number of both preclinical and clinical studies strongly suggest that MC possesses a relatively strong anti-cancer, anti-inflammatory, anti-AIDS, anti-AD (Alzheimer’s disease), anti-PD (Parkinson’s disease), anti-schizophrenia, anti-depressive, and anti-melanogenic effects, all of which are closely associated with anti-PAK1 activity. Furthermore, it is obvious that, unlike FK228, MC passes effectively through BBB (blood brain barrier). Most recently, there emerged a paper by a US group clearly indicating that MC could be a direct PAK1-inhibitor, as is CEP-1347.  Lastly, it has been reported that MC indeed inhibits the growth of MPNST (NF1-deficient cancer) cells. Thus, it would be worth testing its anti-PAK1 activity in vitro first, and then its anti-NF2 (tumor) activity in cell culture as well as in vivo (against human NF tumor xenograft in mice) to get the FDA approval for NF therapy. 

Discussion

Tetracyclin (TC) is an anti-bacterial antibiotic developed in late 1940s, and inhibits the ribosome-based protein synthesis in bacteria, but not in mammals.  Thus, it selectively kills pathognenic bacteria without any serious side effect on mammals. However, bacteria gradually developed TC-resistance, and therefore TC is no longer used nowadays for therapy of infectious diseases.

According to a recent review on minocycline (MC), an old (long-lasting) TC derivative developed in 1961, the antibiotic MC has been successfully used for therapy of a wide variety of infectious diseases and thrombosis as well for more than 4 decades without any serious side effects (1).  However, since MC is now a “generic” drug, and is available on the market extremely inexpensive (100 mg costs only 30 cents), if you take 100 mg twice a day, it would cost you only 60 cents daily.

Furthermore, over 4 decade study has revealed that MC can be used beyond the ordinal antibiotics killing only pathogenic bacteria.  A wide range of other diseases appear to be among targets of MC (1), such as cancer, a variety of inflammatory diseases, AD (Alzheimer’s disease), PD (Parkinson’s disease), schizophrenia, depression, autism, obesity, hyper-pigmentation, and so forth. All of these diseases/disorders are among typical PAK1-dependent symptoms. Thus, there is a good possibility that MC is a PAK1-blocker.

In support of this notion, just like CEP1347 that inhibits both PAK1 and MLK (2), MC inhibits thrombosis (platelet aggregation) (3).  Most interestingly, MC enhances sleep and memory in clinical trials, clearly indicating that unlike FK228, MC passes through BBB (blood brain barrier) (4). In support of this notion, MC is effective for therapy of “cerebral” malaria in mice as well (5).   Thus, it is quite possible that MC would be useful for therapy of brain tumors in general.

How about NFs (neurofibromatosis type 1 and 2)?  Sadly so far no effective FDA-approved therapeutic is available on the market for NF patients as yet, except for propolis, natural PAK1-blockers made by honey bees.  Very recently, a group in Taiwan reported that MC is effective to suppress the growth of MPNST (Nf1-deficient cancer) cells (6). Thus, like propolis such as Bio 30 from New Zealand which has been successful for therapy of both NF1 and NF2 clinically, MC would be potentially useful for NF2 therapy as well. 
 
I should remind you that “Gleevec”, which blocks PAK1 by inhibiting Tyr-kinases (PDGFR/KIT), is also useful for NF therapy (7), but is very expensive. So MC could replace “Gleevec” soon.

References:

1. Garrido-Mesa N, Zarzuelo A, Galvez, J. Minocycline: far beyond an antibiotic. Brit. J. Pharmacol. 169 (2013). 337-352.

2. Neu TV, He, H. Hirokawa Y. et al. The K252a derivatives, Inhibitors of PAK/MLK kinase family selectively block the growth of RAS transformants.

3. Joseph W. Jackson, Affiliation Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America ⨯ Meera V. Singh, Vir B. Singh, et al. Novel Antiplatelet Activity of Minocycline Involves Inhibition of MLK3-p38 Mitogen Activated Protein Kinase Axis. PloS ONE 11 (2016), e0157115. 

4. Besedovsky L, Schmidt EM, Linz B, Diekelmann S, Lange T, Born J. Signs of enhanced sleep and sleep-associated memory processing following the anti-inflammatory antibiotic minocycline in men. J Psychopharmacol.  2017 ; 31(2): 204-210.

5. Apoorv TS, Babu PP. Minocycline prevents cerebral malaria, confers

neuroprotection and increases survivability of mice during Plasmodium berghei

ANKA infection. Cytokine. 2017 ; 90 :113-123.

6. Ko JC, Wang TJ, Chang PY, et al. Minocycline enhances mitomycin C-induced cytotoxicity through down-regulating ERK1/2-mediated Rad51 expression in human non-small cell lung cancer cells. Biochem Pharmacol. 2015 ; 97(3): 331-40.

7. Mukherjee J, Kamnasaran D, Balasubramaniam A, Radovanovic, Zadeh G, Kiehl TR, Guha A. Human schwannomas express activated platelet-derived growth factor receptors and c-kit and are growth inhibited by Gleevec (Imatinib Mesylate). Cancer Res. 2009 ; 69(12): 5099-107.