Cancer – to DIY or not to DIY – Food Pharmacy

Paul Clayton

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Cancer – to DIY or not to DIY

Cancer treatment used to be barbarous. The first weapons in the war against cancer, the nitrogen mustards, were originally developed as weapons of war. Today, cancer treatment is merely terrifying. 

Immunochemotherapy is inherently less destructive than the old chemotoxins, and newer approaches ranging from ancillary CR-3 agonists to the checkpoint inhibitors have major steps forward; but if you read the small print on a Keytruda pack insert, you will still see around 90 adverse effects listed there. 

Successful cancer cells escape immune surveillance by expressing cloaking proteins on their surface which hide them from the T cells that would otherwise identify and kill them. One of the cloaking proteins is called programmed death ligand (PD-L1), and drugs like Keytruda work by targeting PD-L1 so that the immune system can see and attack the cancer cells.

 There is a lot of good and well-funded research going on to identify even more specific (and maybe safer) anti-cloaking targets, from MEX3B (1) to elF5B (2).  Others are combining radiotherapy with immunochemotherapy, as radiation damages cancer cells and makes them more antigenic (3). Combining antimitotics with glycolysis (PFKFB3) inhibitors looks promising (4), and adding post-glycolysis lactate dehydrogenase inhibitors may be even better (5).

But do we really need more magic bullets? Are we pointing our guns in the right direction? Could we, instead, do more on the home front?

Cancer cells are genomically unstable (6). When a diverse mass of cancer cells is attacked, those individual cells with mutations that make them less vulnerable survive preferentially and become parents of the next generation of treatment-resistant cancer cells. This is why most cancers eventually escape from chemotherapy and immunochemotherapy (ie 7). This is, simply, cellular Darwinism.

Perhaps we should be asking instead why cancer has become so very popular, identify the causative factors, and stem the rising tide. In the last 40 years, for example, rates of cancer in adolescents and young adults have increased by up to 30% (8). When you look at their diet, it is not hard to see why.

The ultra-processed diet kills us in various ways (ie 9, 10). By causing chronic inflammation, dysbiosis and hyperinsulinemia, and at the same time depleting us of a range of cancer-protective phytonutrients (11), it is most certainly causing cancer (12).

We cannot afford not to address this. As Karol Sikora pointed out in his clarion 2007 paper (13), cancer care costs everywhere are raging out of control. An ageing, overweight and fundamentally unhealthy population exposed to emerging medical technology in an information-rich, consumer-orientated world, drives up demand for ever (14). 

An ounce of prevention is usually better than a pound of cure.

With cancer costs spiralling we’ll run out of pounds, dollars, euros and yuan long before the ‘cure for cancer’ Joe Biden dementedly promised during the run-up to the last election (15). Big Pharma and their political whores are making hay, but we serfs face a cancer-riddled future if we continue on this well-paved road to perdition.

Prevention, then. 

First step is to restore pre-transitional nutrition (16, 17), a simple strategy which should cut cancer by up to 90% (18, 19) – especially if you stop smoking, and take a little exercise.

That still leaves roughly 10%. These individuals carry genes such as BRCA1 and 2, FAP and MAP and another 50 or more, and have an inherently higher risk of cancer. What hope is there for them?

Perhaps we could turn to mother’s milk. If there is a sweet spot where many different cancerous cells converge and can be killed with kindness, this might just be it. And this is where the Prince of Denmark enters, stage left. 

HAMLET, or Human Alpha-lactalbumin Made Lethal to Tumour cells – it’s a labored acronym – is derived from breast milk. It couples alpha-lactalbumin, a protein that regulates the production of lactose in milk, with oleic acid, a fatty acid produced in humans and olives. The resulting complex might just be the holy grail of oncology; it kills a variety of cancer cells (20), with minimal collateral damage.

Professor Catharina Svanborg, at Lund University, did the early taxonomic work. (I am abusing taxonomy here, in a nod to an earlier Lund graduate.) She then founded Hamlet Pharma Ltd to develop the technology. I wish her the very best of luck in this endeavor, which looks as if it will be a great gift to humanity and worth a Nobel or two. 

Catharina was both lucky and brilliant. It started with a chance observation, but chance favours the prepared mind and I believe she immediately understood the import of her first unexpected findings. I won’t present her milestones in the sequence in which they occurred, but in a way that allows an economic story line.

Briefly, she found that when alpha-lactalbumin (α-LA) is mixed with oleic acid (OA) it unfolds, binds to the OA via van der Waals forces and hydrogen bonds, and forms complexes. The α-LA/OA complexes enter the cell membranes of cells and force the membranes of cancer cells to alter their shape and structure in such a way as to efficiently trigger apoptosis (21-24).

When these complexes are infused into mice (24) or cancer patients (25, 26), cancer cells break down promptly and without adverse effects. And while α-LA (27) and OA (28) have some anti-cancer effects on their own, the combination is super-additive.

When α-LA and OA are complexed, regions in α-LA bind non-specifically to components in cell membranes. The α-LA/OA complex then creates physical stress and local distortion of the cell membrane that normal cells can accept; but cancer cells, which possess specific alterations in their membranes required for faster growth and/or metastatic spread (29-31), cannot.

The α-LA/OA complex causes cation fluxes across the cancer cell membrane (21) possibly due to physical membrane changes combined with the well-known ability of α-LA to bind Ca++, Mg++, Mn++, Na+ and K+. These ion fluxes initiate multi-step sequences which ultimately lead, possibly via the mitochondrial Heat Shock Protein ‘Mortalin’ (32, 35), to apoptosis (33-35).

As the cancer cells die they create an innate immune response in surrounding healthy tissues. This constitutes an additional anti-cancer effect.

α-LA is a very interesting protein indeed. It is a shape-shifter, and can adopt at least 5 different configurations, each with a different functionality (36). Some of these changes are driven by the different cations listed above (22, 36). This may mean that its shape in the cancer cell membrane is not constant but dynamic, and this might also contribute to its ability to cause membrane deformation and cancer cell death.

HAMLET and a semi-synthetic, smaller protein/fatty acid complex (20) are currently undergoing clinical trials. Early reports in bladder cancer and skin papillomas are positive (25), but if you are too impatient to wait out the protracted regulatory procedure you could hack the model and DIY. 

When the headlines first appeared, a black market in human breast milk developed almost overnight. Cancer patients using the social media tag #freezerstash searched online for wetnurses (37), but α-lactalbumin on its own is not enough. Neither is oleic acid. To form an effective cancer killer, these two molecules must be complexed together.

There are two main methods of making α-LA-OA complexes. 

HAMLET was initially prepared by running human α-LA through an OA-conditioned anion exchange column. This would be difficult though not impossible to do in your kitchen. Then it got easier. A second method was published, showing that if you simply mixed α-LA and OA in solution, this worked just as well (38). 

And then BAMLET appeared on the scene. It became clear that cow’s milk was just as good as human milk. Bovine α-lactalbumin could be substituted for human α-lactalbumin and bound to oleic acid to form an anti-tumor complex that did everything HAMLET could do (39-41), and more cheaply. 

In an ideal world the next variant would have been based on sheep’s milk, and called OMLET. Omlet is Afrikaans for Hamlet, but it was not to be. Instead, we got BLAMLET. 

A Beijing team found that a different cow’s milk protein, lactoferrin, worked in the same way as α-lactalbumin, though it was only a tenth as effective (42). The same group then discovered that bovine β-lactoglobulin produced cancer-killing complexes with oleic acid and linoleic acid as well (43). This was highly effective at killing cancer cells – and it may kill the cancer industry too.

 β-lactoglobulin and oleic acid are common food ingredients. Whey protein is approximately 50% β-lactoglobulin by weight (44), olive oil contains 55-80% oleic acid. (I prefer oleic acid to linoleic acid because it will do less damage to your omega 6:3 index). In short, cooking up a cancer cure in your kitchen starts to look feasible.

Whey protein blended with olive oil will, if you follow the recipe (43, 45), produce an emulsion containing β-lactoglobulin / oleic acid complexes. (Whey protein is an excellent emulsifier). Do not blend for more than 40-50 seconds as foaming degrades the protein. Preparation time: approximately 1 hour. You will need: a benchtop centrifuge, an ultra-filtration kit and an iv drip. Total cost on Ebay: $500-700.

You cannot drink the whey / olive oil brew because most of the proteins you ingest will be digested and their functionality lost. Hence the iv drip, which has long beenused to deliver emulsions containing protein and fatty acids. You need to make sure that your ingredients are sterile, for obvious reasons, but the ultra-filtration will take care of that.

Allergy to cow’s milk is clearly a contra-indication; and the course, should you decide to try this, will necessarily be a week or less as serum sickness will otherwise develop.

If you are afraid of needles you may wish to explore the mysteries of the nutrient enema, AKA rectal alimentation. This ancient medical technique is described in a fascinating sub-set of the scientific literature (47-50) and has more recently been abused by the CIA (51), but may still be useful in certain situations.

In either case, proceed at your own risk.

While you’re pondering the options, let’s ask the obvious evolutionary question. Do these tumoricidal complexes have a purpose? They are probably being formed in the body in small amounts at all times, because oleic acid levels in blood remain fairly constant (51) and lactalbumin can be detected at low levels in men and non-pregnant women (52).

Levels of lactalbumin in the blood rise dramatically in the latter stages of pregnancy and during breast-feeding, and one would expect levels of α-LA-OA complexes to rise also. 

The latter stages of pregnancy are characterized by a form of adaptive and partial immunosuppression, which allows the fetal tissues to grow and develop. One could hypothesize that immune changes which might be cancer-permissive at this time (53) are countered by increased levels of lactalbumin / oleic acid complexes in the blood. 

But this is only a hypothesis, and hypotheses are cheap.

This is a guest post. Any opinions expressed are the writer’s own.

References

  1. Huang L, Malu S, McKenzie JA, Andrews MC, Talukder AH, Tieu T, Karpinets T, Haymaker C, Forget MA, Williams LJ, Wang Z, Mbofung RM, Wang ZQ, Davis RE, Lo RS, Wargo JA, Davies MA, Bernatchez C, Heffernan T, Amaria RN, Korkut A, Peng W, Roszik J, Lizée G, Woodman SE, Hwu P. The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression. Clin Cancer Res. 2018 Jul 15;24(14):3366-3376.
  2. Suresh S, Chen B, Zhu J, Golden RJ, Lu C, Evers BM, Novaresi N, Smith B, Zhan X, Schmid V, Jun S, Karacz CM, Peyton M, Zhong L, Wen Z, Sathe AA, Xing C, Behrens C, Wistuba II, Xiao G, Xie Y, Fu YX, Minna JD, Mendell JT, O’Donnell KA. eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer. Nat Cancer. 2020 May;1(5):533-545.
  3. Wilkins A, McDonald F, Harrington K, Melcher A. Radiotherapy enhances responses of lung cancer to CTLA-4 blockade. J Immunother Cancer. 2019 Mar 6;7(1):64.
  4. Mondal S, Roy D, Sarkar Bhattacharya S, Jin L, Jung D, Zhang S, Kalogera E, Staub J, Wang Y, Xuyang W, Khurana A, Chien J, Telang S, Chesney J, Tapolsky G, Petras D, Shridhar V. Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers. Int J Cancer. 2019 Jan 1;144(1):178-189.
  5. Chen YJ, Mahieu NG, Huang X, Singh M, Crawford PA, Johnson SL, Gross RW, Schaefer J, Patti GJ. Lactate metabolism is associated with mammalian mitochondria. Nat Chem Biol. 2016 Nov;12(11):937-943.
  6. Yao Y, Dai W. Genomic Instability and Cancer. J Carcinog Mutagen. 2014;5:1000165. 
  7. Touat M, Li YY, Boynton AN. et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature 580,517–523 (2020).
  8. Scott AR, Stoltzfus KC, Tchelebi LT et al. Trends in Cancer Incidence in US Adolescents and Young Adults, 1973-2015. JAMA Netw Open. 2020;3(12):e2027738.
  9. Bonaccio M, Di Castelnuovo A, Costanzo S, De Curtis A, Persichillo M, Sofi F, Cerletti C, Donati MB, de Gaetano G, Iacoviello L. Ultra-processed food consumption is associated with increased risk of all-cause and cardiovascular mortality in the Moli-sani Study. Am J Clin Nutr. 2021 Feb 2;113(2):446-455.
  10. Levy RB, Rauber F, Chang K, Louzada MLDC, Monteiro CA, Millett C, Vamos EP. Ultra-processed food consumption and type 2 diabetes incidence: A prospective cohort study. Clin Nutr. 2020 Dec 28:S0261-5614(20)30693-2.
  11. Clayton P, Rowbotham J. An unsuitable and degraded diet? Part two: realities of the mid-Victorian diet. J R Soc Med. 2008 Jul;101(7):350-7.
  12. Fiolet T, Srour B, Sellem L, Kesse-Guyot E, Allès B, Méjean C, Deschasaux M, Fassier P, Latino-Martel P, Beslay M, Hercberg S, Lavalette C, Monteiro CA, Julia C, Touvier M. Consumption of ultra-processed foods and cancer risk: results from NutriNet-Santé prospective cohort. BMJ. 2018 Feb 14;360:k322.
  13. Sikora K. Paying for cancer care – a new dilemma. J R Soc Med. 2007 Apr;100(4):166-9.
  14. Bosanquet N, Sikora K. The Economics of Cancer Care. Cambridge: Cambridge University Press, 2006
  15. https://www.youtube.com/watch?v=pB4BxNjMb7Q  (@ 48’35”)
  16. Popkin BM, Gordon-Larsen P. The nutrition transition: worldwide obesity dynamics and their determinants. Int J Obes Relat Metab Disord. 2004 Nov;28 Suppl 3:S2-9.
  17. Popkin BM. Nutrition in transition: the changing global nutrition challenge. Asia Pac J Clin Nutr. 2001;10 Suppl:S13-8.
  18. Rowbotham J, Clayton P. An unsuitable and degraded diet? Part three: Victorian consumption patterns and their health benefits. J R Soc Med. 2008 Sep;101(9):454-62.
  19. Charlton J, Murphy M, editors. The Health of Adult Britain 1841–1994. 2 volumes. London: National Statistics; 2004.
  20. https://cordis.europa.eu/project/id/954360
  21. Hallgren O, Aits S, Brest P, Gustafsson L, Mossberg AK, Wullt B, Svanborg C. Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells). Adv Exp Med Biol. 2008;606:217-40.
  22. Storm P, Klausen TK, Trulsson M, Ho C S J, Dosnon M, Westergren T, Chao Y, Rydström A, Yang H, Pedersen SF, Svanborg C. A unifying mechanism for cancer cell death through ion channel activation by HAMLET. PLoS One. 2013;8(3):e58578.
  23. Nadeem A, Sanborn J, Gettel DL, James HC, Rydström A, Ngassam VN, Klausen TK, Pedersen SF, Lam M, Parikh AN, Svanborg C. Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex. Sci Rep. 2015 Nov 12;5:16432.
  24. Hien TT, Ambite I, Butler D, Wan MLY, Tran TH, Höglund U, Babjuk M, Svanborg C. Bladder cancer therapy without toxicity-A dose-escalation study of alpha1-oleate. Int J Cancer. 2020 Nov 1;147(9):2479-2492.
  25. Ho JCS, Nadeem A, Svanborg C. HAMLET – A protein-lipid complex with broad tumoricidal activity. Biochem Biophys Res Commun. 2017 Jan 15;482(3):454-458.
  26. https://www.prnewswire.com/news-releases/hamlet-pharma-announces-results-of-first-major-clinical-trial-for-a-new-cancer-killing-molecule-300888552.html
  27. Håkansson A, Zhivotovsky B, Orrenius S, Sabharwal H, Svanborg C. Apoptosis induced by a human milk protein. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8064-8.
  28. Giulitti F, Petrungaro S, Mandatori S, Tomaipitinca L, de Franchis V, D’Amore A, Filippini A, Gaudio E, Ziparo E, Giampietri C. Anti-tumor Effect of Oleic Acid in Hepatocellular Carcinoma Cell Lines via Autophagy Reduction. Front Cell Dev Biol. 2021 Feb 5;9:629182.
  29. Galeotti T, Borrello S, Minotti G, Masotti L. Membrane alterations in cancer cells: the role of oxy radicals. Ann N Y Acad Sci. 1986;488:468-80.
  30. Szlasa W, Zendran I, Zalesińska A, Tarek M, Kulbacka J. Lipid composition of the cancer cell membrane. J Bioenerg Biomembr 52, 321–342 (2020).
  31. Zalba S, ten Hagen TLM. (2017) Cell membrane modulation as adjuvant in cancer therapy. Cancer Treat. Rev. W.B. Saunders Ltd.
  32. Pagliarone AC, Castañeda ED, Pedott Santana JP, de Oliveira CAB, Robeldo TA, Teixeira FR, Borra RC. Mitochondrial Heat Shock Protein Mortalin as Potential Target for Therapies Based on Oxidative Stress. Photodiagnosis Photodyn Ther. 2021 Mar 15:102256.
  33. Ho J, Sielaff H, Nadeem A, Svanborg C, Grüber G. The molecular motor F-ATP synthase is targeted by the tumoricidal protein HAMLET. J Mol Biol. 2015 May 22;427(10):1866-74.
  34. Ho JCS, Nadeem A, Svanborg C. HAMLET – A protein-lipid complex with broad tumoricidal activity. Biochem Biophys Res Commun. 2017 Jan 15;482(3):454-458.
  35. Nadeem A, Ho JCS, Tran TH, Paul S, Granqvist V, Despretz N, Svanborg C.Beta-sheet-specific interactions with heat shock proteins define a mechanism of delayed tumor cell death in response to HAMLET. J Mol Biol. 2019 Jun 28;431(14):2612-2627.
  36. Permyakov EA. α-Lactalbumin, Amazing Calcium-Binding Protein. Biomolecules. 2020 Aug 20;10(9):1210.
  37. https://theconversation.com/freezerstash-why-cancer-patients-wont-find-a-cure-in-drinking-human-milk-they-get-online-100123
  38. Permyakov SE, Knyazeva EL, Leonteva MV, Fadeev RS, Chekanov AV, Zhadan AP, Håkansson AP, Akatov VS, Permyakov EA. A novel method for preparation of HAMLET-like protein complexes. Biochimie. 2011 Sep; 93(9):1495-501.
  39. Chaudhuri A, Chattopadhyay A. Lipid binding specificity of bovine α-lactalbumin: a multidimensional approach. Biochim Biophys Acta. 2014 Aug;1838(8):2078-86.
  40. Chaudhuri A, Prasanna X, Agiru P, Chakraborty H, Rydström A, Ho JC, Svanborg C, Sengupta D, Chattopadhyay A. Protein-dependent Membrane Interaction of A Partially Disordered Protein Complex with Oleic Acid: Implications for Cancer Lipidomics. Sci Rep. 2016 Oct 12;6:35015. 
  41. Rath EM, Cheng YY, Pinese M, Sarun KH, Hudson AL, Weir C, Wang YD, Håkansson AP, Howell VM, Liu GJ, Reid G, Knott RB, Duff AP, Church WB. BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state. PLoS One. 2018 Aug 29;13(8):e0203003.
  42. Fang B, Zhang M, Tian M, Jiang L, Guo HY, Ren FZ. Bovine lactoferrin binds oleic acid to form an anti-tumor complex similar to HAMLET. Biochim Biophys Acta. 2014 Apr 4;1841(4):535-43.
  43. Fang B, Zhang M, Tian M, Ren FZ. Self-assembled β-lactoglobulin-oleic acid and β-lactoglobulin-linoleic acid complexes with antitumor activities. J Dairy Sci. 2015 May;98(5):2898-907.
  44. Creamer LK, Sawyer L. β-Lactoglobulin. In: Roginski H. J.W. Fuquay Fox P.F. Encyclopedia of Dairy Sciences. 1st. Academic Press, New York, NY. 2003: 319-386
  45. Fang B, Zhang M, Tian M, Jiang L, Guo HY, Ren FZ. Bovine lactoferrin binds oleic acid to form an anti-tumor complex similar to HAMLET. Biochim Biophys Acta. 2014 Apr 4;1841(4):535-43.
  46. Vitas DBS analyses. In-house data
  47. Tyson WJ. Rectal Alimentation. Br Med J. 1882 Mar 25;1(1108):420-1.
  48. Bliss DW. Feeding Per Rectum. The Medical Record, NY, July 15, 1882
  49. No author. Rectal Alimentation. Nature (1926). 118;858-9
  50. Mesas Burgos C, Ehrén H, Finkel Y. Neonatal short bowel syndrome: ‘rectal feeding’ in order to stimulate intestinal growth. Acta Paediatr. 2008 Aug;97(8):1140-2.
  51. https://www.theguardian.com/us-news/2014/dec/09/cia-report-rectal-feeding-detainees
  52. Kleinberg DL. Human alpha-lactalbumin: measurement in serum and in breast cancer organ cultures by radioimmunoassay. Science. 1975 Oct 17;190(4211):276-8.
  53. Kareva I. Immune Suppression in Pregnancy and Cancer: Parallels and Insights. Transl Oncol. 2020 Jul;13(7):100759

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