Science paper The anticancer properties of harmine and its derivatives

[Prima Materia]

"Abstract This review aims to provide information about the anticancer potential of harmine, a b-carboline alkaloid that was initially isolated in 1847 from the seeds and roots of Peganum harmala L. Various studies have revealed that it possesses a wide range of therapeutic qualities, including anti-inflammatory, antibacterial, antiviral, antidiabetic, and, most notably, anticancer effects. This review discusses the anticancer capabilities of harmine and its derivatives against malignancies such as breast cancer, lung cancer, gastric cancer, colon cancer, glioblastoma, neuroblastoma, liver cancer, pancreatic cancer and thyroid cancer. Harmine uses mechanisms such as apoptosis and angiogenesis inhibition to fight cancer cells. It also influences the cell cycle by inhibiting specific cyclin-dependent kinases and slowing tumor cell proliferation. Synergistic effects have also been observed when harmine is used in combination with other anticancer medications. Harmine has the potential to be a potent anticancer medication that can help in the fight against cancer"
A. A. Timbilla R. Havelek M. Rezacova Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Simkova 870, 500 03 Hradec Kra´love´, Czech Republic R. Vrabec J. Chlebek L. Cahlikova (&) Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kra´love´, Czech Republic e-mail: cahlikova@faf.cuni.cz G. Blunden School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, Hampshire PO1 2DT, UK

 

[Nydex]

That's pretty exciting stuff. Molecular engineering is such a fascinating science. If the chemical modifications at positions C2, C7, and N9, turn out to almost completely remove the neurotoxicity while preserving the cancer-killing properties, and also keeping the resulting molecule safe in-vivo (i.e. it can be safely metabolized and excreted by the body without causing liver/kidney damage), it might be an enormous breakthrough in oncology and might replace conventional cancer treatments like 5-fluorouracil.

In a day and age where cancer is more and more prevalent, taking an increasing number of lives every year, we need something like this. Harmalas ftw!

 

[Prima Materia]

That's pretty exciting stuff. Molecular engineering is such a fascinating science. If the chemical modifications at positions C2, C7, and N9, turn out to almost completely remove the neurotoxicity while preserving the cancer-killing properties, and also keeping the resulting molecule safe in-vivo (i.e. it can be safely metabolized and excreted by the body without causing liver/kidney damage), it might be an enormous breakthrough in oncology and might replace conventional cancer treatments like 5-fluorouracil.

In a day and age where cancer is more and more prevalent, taking an increasing number of lives every year, we need something like this. Harmalas ftw!

Pure Gold, Gold of Esfand

 

[The Sofa Traveler]

Pure Gold, Gold of Esfand

 

[Nydex]

Pure Gold, Gold of Esfand

Beyond the streamer, I don't know what Esfand is, nor what his gold is, can you explain a bit more

 

[blig-blug]

I don't know what Esfand is

A Persian name for Peganum harmala.

 

[murklan]

Great that more work is being done with this interesting plants medicines!
But I'm also curious of potential concerns regarding toxicity since I've seen it mentions of hepatoxicity here and there. I don't grasp the full picture but others maybe can. Check this out: https://www.benchchem.com/product/b12426567?utm_src=pdf-body-href And the chapter : Toxicological Profile of Harmane and Its Derivatives: An In-depth Technical Guide.
Perhaps it's the 'usual', really high amounts for extended time on poor rats :/

 

[Nydex]

Great that more work is being done with this interesting plants medicines!
But I'm also curious of potential concerns regarding toxicity since I've seen it mentions of hepatoxicity here and there. I don't grasp the full picture but others maybe can. Check this out: https://www.benchchem.com/product/b12426567?utm_src=pdf-body-href And the chapter : Toxicological Profile of Harmane and Its Derivatives: An In-depth Technical Guide.
Perhaps it's the 'usual', really high amounts for extended time on poor rats :/

Yeah that's a fair concern, but is Harmane and Harmine the same thing? I thought they were two different alkaloids, both present in the seeds. Or am I mistaken?

 

[The Sofa Traveler]

But I'm also curious of potential concerns regarding toxicity since I've seen it mentions of hepatoxicity here and there.

Nevertheless, in the book Harmal : The Genus Peganum, I found several occurrences about hepatoprotective properties of harmal but none about hepatotoxicity, except one in the references but not directly related to harmal. At least, vasicinone, contained in harmal seeds seems to show hepatoprotective effects. Here are a some quotes from hepatoprotective and hepatoprotection occurrences I found in the book (for what they are worth) :

p.106
Vasicinone possessed hepatoprotective (Sarkar et al. 2014), antiasthmatic (Nilani et al. 2009), and anticancer (Wang C.H. et al. 2015) properties (Figure 6.58). Its presence was confirmed in P. harmala (Pulpati et al. 2008) and P. multisectum (Liu 2011) (Figure 6.59).

p.139
Relative to the pharmaceutically induced diabetic rat controls, the animals with diabetes that also received the harmal showed significant, dose-dependent reduction in the abnormally elevated glucose, lipid abnormalities, malondialdehyde—a marker of oxidative stress, alanine transaminase—whose elevation is associated with hepatic stress, aspartate trans-aminase (also known as SGOT), gamma-glutamyltranspeptidase—an enzyme associated with hyperoxidation states, bilirubin—the product of red blood cell lysis, and glycated hemoglobin, while the total antioxidant capacity in the harmal-treated
groups increased. The results showed the antidiabetic effects of harmal to encompass serum glucose reduction, enhanced antioxidant free radical scavenging, prevention of glycation products, and hepatoprotection, suggesting multifaceted heuristic applications for diabetology.

pp.169-170
Hamden et al. (2008a) investigated the putative liver-protective qualities of both ethanol and chloroform extracts of P. harmala on diseases induced by thiourea in adult male rat (Figure 7.16). Thiourea is a carcinogen. Its effects on body weight, thyroid function, and endocrine cancer parameters have been recorded. Hepatoprotection was related to aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum bilirubin. Since both ethanolic and chloroform harmal extracts were able to revert neuronspecific enolase (NSE) and thyroglobulin (TG) levels to normal following their post-thiourea elevation, the hepatoprotective potency of harmal was proven.
In an independent investigation conducted in Tunisia, Bourogaa et al. (2015), also evaluated a harmal extract as putative hepatoprotector in rat, in this case after exposure to ethanol in water 35% (4 g/kg/day) for 6 weeks. Some animals also received the harmal extract by i.p. injection, 10 mg/kg, daily, and control rats received i.p. saline. The chronic ethanol exposure increased lipid peroxidation as measured by increased thiobarbituric acid reactive substances (TBARS) in liver, with concurrent disturbances in antioxidant defense, hepatic superoxide dismutase, catalase, and glutathione peroxidase. Harmal injection blocked the lipid peroxidation and attenuated the antioxidant disturbance.

p.176
In a subsequent work (Hamden et al. 2009) the group was able to replicate its results and suggest that the anti-aging
mechanisms, antioxidant activity, and hepatoprotection of both harmal and caloric restriction possibly could be attributed to their ability to increase E2 level, which as an antioxidant acts as a scavenger of ROS.

 

[blig-blug]

Yeah that's a fair concern, but is Harmane and Harmine the same thing? I thought they were two different alkaloids, both present in the seeds. Or am I mistaken?

It's not the same. Whatever toxicity must be dose-related, as harmane is found not only in coffee and other foods, but also produced endogenously.

in the book Harmal : The Genus Peganum

In that same book, this is mentioned in p. 96 as a potential problem with harmane:

Harmane was looking better and better, except for one issue. It seems that just as harmaline was roped into the role of poster child for causing tremors, complete with a harmaline tremor scale named in its honor, harmane is associated with something called harmane-induced amnesia (Nasehi et al. 2010, 2012, 2013a,b).

I imagine that, like harmaline with tremors, this will be an issue at larger doses.

 

[The Sofa Traveler]

In that same book, this is mentioned in p. 96 as a potential problem with harmane:

I imagine that, like harmaline with tremors, this will be an issue at larger doses.

Yes but I just searched about hepatoxicity to reply to @murklan worries on this specific topic.

 

[blig-blug]

Yes but I just searched about hepatoxicity to reply to @murklan worries on this specific topic.

I know, I was only sharing what I had found about it, as I was about to post about it when your post showed up

 

[Transform]

is Harmane and Harmine the same thing? I thought they were two different alkaloids

Correct - harmane (or, imo, better) harman, lacks the 7-methoxy group that harmine has.