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J Acupunct Res > Volume 32(1); 2015 > Article
Cho, Lee, Yoon, Lim, Lee, Choi, and Lee: The Antitumor Mechanism and Effects of Tetrodotoxin: a Literature Review
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Abstract

Objectives:

The purpose of this study is to explore the antitumor mechanism and effects of tetrodotoxin through a literature review of experimental and clinical studies.

Methods:

Medical databases, including The Cochrane Library, Pubmed, NDSL, RISS4u and National Assembly Library, were searched for relevant articles published from January 1, 2000 to October 31, 2014 using the keywords ‘tetrodotoxin’, ‘cancer’ and ‘tumor'. The results were classified into experimental studies(in vitro and in vivo) and clinical studies. Analysis of the results was conducted on several research areas including the mechanism, antitumor effect and adverse effects of tetrodotoxin(TTX).

Results:

A total of 34 experimental studies(32 in vitro and 2 in vivo) and 3 clinical studies were found in the search. Most of the experimental studies suggested blocking of voltage-gated sodium channels in metastasis of tumor cells as the main antitumor mechanism of TTX. The most common type of cancers mentioned in the experimental studies were prostate and breast cancer. All of the clinical studies were on the application of TTX on moderate to severe cancer-related pain. No adverse effects of TTX were reported in in vivo studies but mild to moderate adverse events were reported in clinical studies.

Conclusions:

The results show that tetrodotoxin, which is the main component of Tetraodontidae(commonly known as pufferfish) poison, could be clinically used for antitumor therapy. However, further studies should be conducted on its safety.

Fig. 1.
Flowchart of study selection process
acupunct-32-1-97f1.gif
Fig. 2.
Number of researches according to published year of in vitro studies of TTX
acupunct-32-1-97f2.gif
Fig. 3.
Number of researches according to cancer type of in vitro studies of TTX
acupunct-32-1-97f3.gif
Table 1.
Summary of in vitro Studies about Antitumor Effect of TTX
Cancer type Study Cell Species TTX Na+channels Other mechanism Process
Inhibit Promote No effect
Non small cell lung cancer 2013/Campbell3)TM H460 0.5 μM Na(v) 1.7 Invasion
2007/Roger S4) H23, H460, Calu-1 Human 30 μM Not specific Invasion Proliferation, migration
Small cell lung cancer 2005/Onganer PU5) H69, H209, H510 Human 5, 10, 100, 1,000 nM Not specific Endocytosis
Neuroblastoma 2007/Kawaguchi A6) NG108-15 0.1 μM Na(v) 1.7 INa
Glial tumor 2001/Kraft R7) 1321N1, A172 Human 300 nM Not specific INa
Colon cancer 2010/House CD8) SW620, SW480, HT29 Human 10, 30 μM Na(v) 1.5 Invasion
2004/Maselli MA9) colon tissue Human 2 μM Not specific Contraction
Ovarian cancer 2010/Gao R10) Caov-3, SKOV-3 Human 30 μM Na(v) 1.5 Migration, invasion Proliferation
Breast cancer 2010/Fraser SP11) MDA-MB-231 Human 10 μM Not specific E2-cell adhesion
2010/Chioni AM12) MDA-MB-231 Human 5, 10 μM nNa(v) 1.5 Migration
2009/Krasowska M13) MDA-MB-231, MCF-7 Human 1 μM Not specific Endocytosis
2009/Gao R14) MDA-MB-231 Human 30 μM nNa(v) 1.5 MMP-9 Invasion
2009/Gillet L15) MDA-MB-231 Human 30 μM Na(v) 1.5 Invasion
2009/Tran TA16) MDA-MB- 231 Human 30 μM Na(v) 1.5 Invasion
2005/Fraser SP17) MDA-MB- 231 Human 10 μM nNa(v) 1.5 Motility, endocytosis, invasion
2004/Roger S18) MDA-MB-231 Human 30 μM Not specific Proliferation
2003/Roger S19) MDA-MB-231 Human 30 μM Not specific Invasion Migration, proliferation
Prostate cancer 2009/Nakajima T20) PC-3 Human 1, 10 μM Na(v)1.6, 1.7 Migration, endocytosis
Mat-LyLu Rat Na(v) 1.7 INa
2007/Uysal-Onga ner P21) PC-3M Human 500 nM Na(v) 1.7 Migration, endocytosis > invasion
2008/Ding Y22) Mat-LyLu Rat 500 nM Not specific Migration
2008/Palmer CP23) Mat-LyLu, PC-3M Human 1 μM Not specific Adhesion
2006/Scorey N24) PC-3 Human 5 nM Not specific Motility, migration
2006/Brackenbury WJ25) Mat-LyLu Rat 1 μM Na(v) 1.7 Feedback mechanism involving PKA Migration
2005/Mycielska ME26) PC-3M Human 2 μM Not specific INa
2004/Bennett ES27) C4, C4-2 Human 1 μM Not specific Migration, invasion
2003/Fraser SP28) Mat-LyLu, AT-2 Rat 1 μM Not specific Motility Proliferation, viability
2003/Mycielska ME29) Mat-LyLu, AT-2 Rat μM 1 Not specific Endocytosis
2001/Djamgoz MBA30) Mat-LyLu, AT-2 Rat 1, 5 μM Not specific Migration
2000/FraserSP31) Mat-LyLu, AT-2 Rat 6 μM Not specific Proliferation
Melanoma 2009/Carrithers MD32) THP-1 Human 300 nM Na(v) 1.6, not Na(v) 1.5 Invasion Migration
HTB-66 Na(v) 1.6
Rhabdom yosarcoma 2006/Randall A33) SJ-RH30 Human 1 μM Na(v) 1.4 INa
Neoplastic mesotheli al cells 2006/Fulgenzi G34) MPM Human 2 μM Na(v)1.2, 1.6,1.7 Migration Cell viability, proliferation, apoptosis
Table 2.
Summary of in vivo Experimental Studies about Antitumor Effect of TTX
Cancer type Study Species Inoculated cell Inj. TTX dose Total number of inj. Mechanism Result Adverse effect
Prostate cancer 2012/Yildirim S35) Rat Mat-LyLu s.c. 200 nM, 1 ml 13/every other day Nav channel - maybe Na(v)1.7 The number of lung metastasis is reduced(~44 % reduction) and that lifespan is significantly improved. no
Ehrlich ascites carcinoma 2012/El-Dayem SM36) Mice 2.5×106 EAC/ml IP 1/20 LD 6 over 2 weeks Antitumor biochemistry 1. Significant decrease in the mean tumor weight and an increase in the cumulative mean survival time
2. Reduced the elevated liver tumor markers(caspase-3, TNF-α)
3. Increased liver antioxidant enzymes(SOD, GST, GSH)
no
Table 3.
Summary of clinical trials about TTX on cancer-related pain patients
Study Design Patient information Intervention Comparison Outcome measures Result
2007/Hagen NA37) A phase II (a, open-label, multi-dose efficacy Severe cancer pain
Total 31 treatment (n=24)
5 groups
1) 7.5 μg bid
2) 15 μg bid
3) 22.5 μg bid
4) 30 μg bid
5) 30 μg tid × 4 days
No BPI-SF Persistent responders(n =13)
Trasient responders(n=4)
vs Non-responders (n=14)
With a 33 % reduction in the intensity of worst, average, or current pain for at least two consecutive days.
NPS Change proportionally to the dose of TTX (r2 = 0.698, p = 0.078)
More sensitive to TTX: characteristics of burning pain, dull pain, and cold pain
Response to pain Somatic and visceral pain(9 of 11) > neuropathic pain(8 of 20)(r2 = 3.465, p = 0.0627)
Opioid use Reduction of total daily dosages of opioids for more than two consecutive days: 12 of 31 treatments(39 %)
The reduction in opioids: 20~100 %
Period: 3–12 days
Not associated with the dose of TTX
2008/Hagen NA38) Multicenter, randomized, double-blind, Placebo-controlled, parallel Moderate to severe cancer pain
n = 77
TTX 30 μg bid X 4 days Placebo (not specific ally mentioned) Proportion of responders 16 of 38 patients in the TTX arm(42 %) and 12 of 39 in the placebo arm(31 %).(p = 0.425)
MPQ 14 responders of 31 to TTX and 10 of 27 to placebo. p=0.719
NPS 10 responders of 18 to TTX and 11 responders of 18 to placebo. p=1.000
Onset of TTTX After 1~4 days of treatment
Average duration of analgesia TTX 19.5±14.3 days, placebo 18.0±12.9 days, ranging from 4 to 42 days
Response to pain Response to TTX: neuropathic 44 %, non-neuropathic 44 %
Response to placebo: neuropathic 18 %, non-neuropathic 27 %
Post hoc analysis With a responder experiencing either improvement of pain or significant fall in opioid use, along with improvement of quality of life, 17 of 38(45 %) were responders to TTX and 8 of 39(21 %) were responders to placebo(p=0.043)
2011/Hagen NA39) Open-label longitudinal trial Moderate to severe cancer pain
n = 45
TTX 30 μg bid X 4 days
When pain returned, re-evaluation for re-treatment
No Number of patients: responder, non-responder Of the 41 evaluable patients, 16 were responders, 5 were clinical responders, and 20 were non-responders to TTX at completion of treatment.
Duration Average duration of pain relief: 20 days for all subsequent cycles mean total duration of TTX: 105±86 days(ranging 20~400 days)
2526 patient-days in total
Table 4.
Adverse effect of TTX in clinical trials
Study Adverse effect
Number / severity Common SAE related to TTX
2007/Hagen NA37) Total 531 / 98 % mild~mo derate. Paresthesia, hypesthesia dose-de pendent manner 2 people: ataxia
1 person: anxiety, wobby legs, emenopausal syndrome(hot flushes) exaggeration
⇒ withdraw
2008/Hagen NA38) TTX: total 570/mild 442, moderate 99, severe 29
Placebo: total 216 / mild 173, moderate 26, severe 17
Tingling, numbness, other transient sensory symptoms 1 person: transient ataxia
1 person: transient moderate dysphagia
⇒ withdraw
2011/Hagen NA39) Total 45 / mild(82 %), moderate (13 %) Nervous and gastrointestinal systems 1 person: hypertension, dizziness
VI.
VI.

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