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.
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, 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.
