Is Heparin an off-label drug for cancer?

Research is consistently showing that Heparin (especially low-molecular weight heparin) can restrict angiogenesis, cancer cell growth, proliferation and metastasis of cancer cells, improving cancer survival in patients.

Heparin and Blood clotting

Heparin is a natural Glycosaminoglycan, or GAG, most usually isolated from pig intestines and is usually prepared as a sodium salt. Heparin is classified into two types, unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH).

Heparin can come from other sources, one being snail mucus. Heparin contains antithrombin, an anticoagulant. It is a widely-used blood thinner, used to prevent or break down blood clots in the veins, arteries or lungs.

Its usage in medicine is increasing dramatically; in 2020 the global Heparin market was US$8.82 billion. Heparin is considered as one of the most critical life-saving drugs available. With Covid-19 and its blood clotting side-effects, the market is booming with a 50 per cent increase projected over the next 6 years..

Heparin and cancer

Heparin is frequently used as an anticoagulant when cancer patients develop thromboembolism. Observational studies suggest that cancer patients treated with either unfractionated or low-molecular weight heparin survive longer than patients treated by other anticoagulants, especially patients in the early stage of the disease. The action of Heparin seems to involve everything from a restriction of angiogenesis to an inhibition of metastasis. This seems to occur through blocking of P- and L-selectin, which inhibits both metastasis-promoting enzymes and angiogenesis (1).

In a recent review (2) researchers presented evidence that heparin could affect the angiogenesis, proliferation, migration, adhesion and invasion of cancer cells via multiple mechanisms, the main ones being ‘inhibition of heparanase, P-/L-selectin, angiogenesis, and interference with the CXCL12-CXCR4 axis’. Heparin is known to bind to proteins and is thus able to regulate a wide range of enzymatic reactions in the body.

While lowering platelets is known to restrict cancer growth and metastasis (platelets act as a bridge connecting cancer cells to the endothelial layer, thereby enhancing cancer cell attachment and metastasis), the anticancer activities of Heparin are far more than just platelet lowering benefits. A number of studies show that Heparin reduces the growth of cancers through inhibiting cancer cell growth factors and/or angiogenesis. It also limits lymphangiogenesis. This is important because the majority of cancer cells spread through the lymph - a number of studies show Heparin can limit the generation of both blood and lymph supplies to cancers (3).

Lung cancer

One study, a multi-center clinical trial (4), where 277 small cell lung cancer patients received subcutaneous heparin over a 5-week period led to substantially improved survival rates when compared to the group having no treatment. After one year a third more people had survived; after 3 years 50 per cent more had survived.

Breast and Ovarian cancer

In several studies it seems that LMWHs are better than Unfractionated-Heparins at increasing survival. In a double-brind Clinical Trial with Breast and pelvic cancers, 2 year postoperative survival increased more with LMWHs - death rates after 2 years with UFH were 37.5 per cent, but only 24 per cent for those on LMWHs (5).

In mice given breast cancer, the use of LMWH with adriamycin cut metastasis to the lungs, increased cancer cell death and reduced the expression of VEGF significantly (6).

Heparin and Cancer Stem Cells

In several studies, Heparin has shown the ability to prevent cancer recurrence by attacking cancer stem cells. For example, cell surface proteoglycans bearing sulfated glycosaminoglycan chains are known to play a critical role in the regulation of stem cell fate and a modified Heparin was found to inhibit Colorectal Cancer Stem Cells in vivo and in vitro (7).

Overall

Because Heparin is so widely used, the reality is that the results for increased survival times and rates are real life figures, not laboratory studies showing possible potential. Heparin does increase survival times in real life. While it can have health risks, it's use does seem capable of benefitting almost every cancer patient.

Warning

Heparin can cause low platelets in the blood. This is termed thrombocytopenia. This can promote more blood clots and can be a fatal condition; it can arise from any form of Heparin, and any dosage. However, even where people are taking Heparin, the drug may not be the cause of low platelets as other factors can produce the same effect.  Bleeding can be caused during the use of Heparin, or after it has been stopped.

Using other medicines at the same time can increase the risk of bleeding - for example,  aspirin and other NSAIDs such as ibuprofen, naproxen, celecoxib, diclofenac, indomethacin and others. Even some natural compounds (for example, fish oils, turmeric, garlic, ginger) can increase risk. You  should tell your doctor what else you are taking, if you are about to use Heparin. 

Go to: How to build an off-label drugs protocol for cancer

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References

1. Heparin as an inhibitor of cancer progression; Lubor Borsig; Prog Mol Biol Transl Sci 2010;93:335-49.

2. The anti-cancer properties of heparin and its derivatives: a review and prospect; Cell Adh Migr 2020; 14(1): 118–128

3. Targeting lymphangiogenesis to prevent tumour metastasis; M G Achen, G B Mann, S A Stacker; Brit J Cancer; 2006 May 22;94(10):1355-60

4. Lebeau B, Chastang C, Brechot JM, et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. Cancer. 1994 July; (1) 74:38–45

5. Von Tempelhoff GF, Harenberg J, Niemann F, et al. Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery. Int J Oncol. 2000;16(4): 815–824.

6. Yin W, Zhang J, Jiang Y, et al. Combination therapy with low molecular weight heparin and Adriamycin results in decreased breast cancer cell metastasis in C3H mice. Exp Ther Med. 2014;8:1213–1218

7. Boothello RS, Patel NJ, Sharon C, et al. A unique nonsaccharide mimetic of heparin hexasaccharide inhibits colon cancer stem cells via p38 MAP kinase activation. Mol Cancer Ther. 2019;18:51–61.