Phlorizin & Phloretin: a powerfull glucose transport inhibitor

Summary 

I know and like Phloretin since long time ago but today I came across a very interesting (old) patent that is based on Phlorizin (a derivative of Phloretin) as an anti cancer treatment. Based on the science behind, safety and case reports, I think this is very interesting and below I will share the information I find most relevant from this patent.

Phloretin/Phlorizin, are very well know Glut1, SGLT1 and SGLT2 inhibitors. These are transporters responsible for transporting glucose into the the cells. For example, glucose symporter SGLT1, co-transports one glucose molecule into the cell for every two sodium ions it imports into the cell. In the cancer cells, some of these transporter are over expressed and their inhibition will lead to energy depletion or may even lead to the death of the cancer cell. Indeed, malignant cells are very much dependent on glucose and when deprived of glucose are unable to maintain their energy (ATP) levels for periods longer than four hours whereas normal cells have no difficulty in maintaining their ATP levels in the absence of glucose (Biochem et Biophysica Res Comm. 82:787, 1978). (Ref). As a result, if not killing the cancer cells,  Phlorizin or Phloretin can at least increase the effectiveness of chemotherapies or other anti cancer therapies by lowering the drug resistance capabilities of cancer cells.

Phloretin/Phlorizin are safe substances and are natural phenols found in apple tree leaves. “One need not fear giving an excessive quantity of phlorizin, however, since this substance has proven to be non-toxic and is rapidly excreted in the urine.” (Ref.)

Apple Polyphenols and Longevity http://www.lifeextension.com/magazine/2012/4/Apple-Polyphenols-Longevity/Page-01

Case reports (from the patent Ref.)

EXAMPLE 1

A thin female 57 years of age entered with sarcoma of duodenum resected 3 years prior. Patient was jaundiced and work up indicated obstruction of common bile duct. Tumor was debulked around porta hepatis and cholecystojejunostomy was done. Patient was then given life time dose of radiation and chemotherapy. Pathology report of patient was a leiomyosarcoma. About one year later, the tumor recurred in the umbilical area requiring further debulking at which time large portion of abdominappleal mass was resected.

Further debulking was done from the abdominal wall, transverse colon and hepatic region. The tumor was not possible to completely resect at any surgery and each time the lesion was more extensive. The patient again became jaundiced and another laparotomy with debulking was performed. A T-tube was placed in the common duct and a gastroenterostomy was performed.

The patient was treated with antibiotics for cholangitis and infection of abdominal wall wound. She was then started on phlorizin given continuously for 12-24 hours with local heat. Systemic temperature rose to 40° C. Vinblastin and Mitomycin C were given I.V. in very small doses. The entire tumor mass became necrotic. Massive necrosis of necrotic tumor became liquified and infected and have required multiple drainages with catheters placed by radiographers under x-ray control. Bowel wall which was replaced by nectrotic tumor tissue has communicated with a large intraabdominal abcess which has been drained. Sepsis is now being controlled. CT scans show multiple areas of tumor liquification and cavitation. The patient’s survival with large necrotic masses is questionable but patient is being supported and sepsis seems under control.

EXAMPLE 2

A 51 year old female had a low anterior resection for cancer of rectum. At time of surgery, hepatic metastases were discovered. Had full course of radiation to pelvis, post surgery. She was treated with 5 FU, Mitomycin C and Novotrome without response. Was starated on 8-12 hour phlorizin plus the same chemotherapeutic agents. Made an immediate response with regression of tumor and no further bowel obstruction.

EXAMPLE 3

A 57 year old male had a melanoma over right scapula removed. There was a local recurrence and a local infection with paraincisional melanosis. This was removed with lymph nodes. Pathological diagnoses was Clark level two melanoma. 7 years later, a cerebral recurrence was found. There were two lesions in frontal lobes and one in parietal area. Was treated with radiation without response. All therapy was then abandoned and the patient was told he had 60 days to live.

The patient was started on small doses of Vincrestine, methyl CCNU and received phlorizin by bolus 5 grams and mild heat to head by RFTT. There was a 50% reduction of lesion by NMR scan. NMR scan of brain was negative. He had a recurrance and was treated but chemotherapy omitted. The lesion did not respond and patient died.

EXAMPLE 4

46 year old female developed a melanoma of the right leg during pregnancy. An excision of primary with lymph node desection and removal was done. Pathology reported that lymph nodes were positive for melanoma. Metastases appeared in head and lungs. Patient was placed on Vincristine and Precarbizone. Severe pain in abdomen probably caused by hemorrhage into a liver mets. She was treated with a bolus of 5 grams o±phlorizin and decadron to lower any possible inflamatory response from necrotic tumor tissue along with RFTT of 50 watts to head and the chemotherapy which had previously been unsuccessful. Vincristine Methyl CCNU and procarbozine was restarted in small doses. The lesion in her brain completely resolved on CT scan. The liver and abdominal diseases had increased and patient died in June of liver and abdominal disease without any recurrance in the head.

EXAMPLE 5

38 year old female developed a melanoma of left axilla which was widely excised with adjacent lymph nodes. Lymph nodes were negative for metastases. She developed plural effusion with multiple nodules in left lung. Received 50.0 mg 5 F.U. and 5 mg. mitomycin C intraplurally. Heated with 100 watts R.F.T.T.. Given vincrestine procarbozine CCNU but did not respond. Chest was drained again in September. Received same treatment plus phlorizin over 12 hours. Responded and now is tumor free for past 11 months.

EXAMPLE 6

A 39 year old woman presented with total obstruction from stomach and a large bowel fistula from previous surgery. She was unable to take any food by mouth. She underwent treatment with R.F.T.T. to area of obstruction after 8 hours of continuous phlorizin infusion. Small doses of chemotherapy were also administered I.V. Patient responded with disappearance of complete gastric outlet obstruction. She is now on full diet and the Fistula has spontaneously closed.

EXAMPLE 7

Patient had carcinoma of breast and previous mastectomy but experienced a large recurrence in the axilla. Because of a generalized vasculitis poorly understood she did not receive chemotherapy but only received phlorizin and heat treatment. She was given a bolus containing 2.5 grams of phlorizin and 75 watts of R.F.T.T. to axilla. Lesion dried up and CT scan was negative.

EXAMPLE 8

34 year old male had a resection of sigmoid and descending colon for cancer of colon. Pathological report described perivascular invasion, lymph node invasion and diffuse periotoneal seeding. All lymph nodes could no be removed. Was treated with 5FU Mitomycin and a bolus of phlorizin. Now has normal CT scan of liver and abdomen. C.E.A. 2.8 and has remained tumor free for 1 year.

EXAMPLE 9

54 year old female with cancer of breast amputated and was placed on chemotherapy and tomoxifen and local radiation. There was a metastases to the 4th ventricle of the brain on CT scan. Patient told no treatment possible and was sent to a terminal cancer hospital.

Was treated with mild heat, phlorizin and decadron without chemotherapy. CT scan now negative and patient remains well.

EXAMPLE 10

62 year old executive had adenocarcinoma of lung with metastases to brain. Three separate lesions appeared in brain on CT and NMR scans. Brain was radiated without response. Lung also radiated without response. Patient was started on 5FU mytomycin and phlorizin. CEA was 8.2. Scan has improved and only 1 small lesion is now visable in brain and 2 have disappeared. Lung lesion has disappeared. No other soft tissue metastases.

EXAMPLE 11

Primary tumor in colon was resected. Patient underwent liver resection for right hepatic metastatic colon cancer. No other tumor seen. Developed recurrent bowel obstruction and peritoneal seeding. Repeated bowel obstructions respond each time to chemotherapy and phlorizin. Laparotomy with a colostomy slowed massive tumor regression. Has improved long term survival.

EXAMPLE 12

56 year old man had cancer of rectum resected. Recurrance three years later in abdomen was treated with a bolus, heat mitromycin and 5FU. Patient developed renal shut down from obstructed ureters. There were liver metastases and abdominal tumor present. Patient was given 8-12 hour phlorizin plus chemotherapy as above and has responded with tumor regression and ureter is no longer obstructed.

EXAMPLE 13

78 year old female had anterior resection for cancer of rectum. She developed a recurrance one year later with radiation to pelvis. No response occured and the bowel was obstructed so a laparotomy was done and an end colostomy performed. Liver metastases were found. Laparotomy and exenteration was done for colovesical fistula. Biopsies were all positive for cancer post exenteration. Patient was treated with 8 hour infusion of phlorizin. Chemotherapy and heat were administered. All biopsies turned negative and there was no evidence of pelvic cancer. Pelvic biopsies were negative Liver metastases remain stable.

EXAMPLE 14

Nasopharangeal cancer treated by radiation and chemotherapy. Pathology was a poorly differentiated squamous cell carcinoma. Lesion spread to both sides of neck. Progressed on chemotherapy. Phlorizin was added by bolus to regime. Patient progressed very slowly. Eight hours of phlorizin was instituted with chemotherapy. Tumor regressed by 80%.

EXAMPLE 15

58 year old female had a right colon resection for carcinoma. The cancer had perforated the bowel wall and there was peritoneal seeding visable. All of the tumor could not be resected. CEA was 13.9 Was treated postoperatively with 5 FU Mitomycin C and phlorizin infusion plus mild heat. Last CT scan was negative for tumor and C.E.A. remains at low level of 3.0.

EXAMPLE 16

80 year old female with massive liposarcoma of left lower leg. Patient has had repeated resections of tumor mass of left lower leg. Patient was injected with mitomycin C and Vinblastin with phlorizin. Because of the shortage of phlorizin, it was injected intralesionally and a tourniquet applied to prevent reabsorption. The lesion has resolved with a 90% regression in tumor size. Requires occasional therapy with heat RFTT and chemotherapy but has not required further surgery.

EXAMPLE 17

48 year old female who had upper G.I. discomfort. She had been working with x-rays for 20 years. Exploratory laparotomy revealed cancer of stomach with diffuse metastases over peritoneum. The patient gradually deteriorated and developed partial bowel obstruction. She received 8-12 hours phlorizin infusion plus 5FU and mitomycin C and RFTT to area of obstruction. Obstruction resolved and went home to Texas. Returned 6 weeks later with another obstruction. Retreated. Mass reduced in size and obstruction overcome. Responds well to treatments.

EXAMPLE 18

54 year old obese female with metastases hypernephroma to brain, scalp and lungs. Primary tumor had been removed some years previously. Patient had failed chemotherapy and was dying. Phlorizin given in bolus of 2 grams with Lonidamine I.V. Heat given to head with conductive R.F.T.T. of 50-100 watts. Necrosis of tumor occurred immediately and patient went into acute cerebral edema requiring immediate neurosurgical decompression. The necrotic tumor was scooped out from brain. Pathology report confirmed that dead tumor tissue had caused acute edema. Tumor of scalp also became necrotic and disappeared leaving a scar biopsy free of tumor. CT scan now confirm that tumor in head had disappeared. Patient now alive and well.

EXAMPLE 19

37 year old male with massive liver cancer. The biopsies disclosed a carcinoid tumor but a search for the primary tumor did not disclose any intestinal primary. He was operated upon and the tumor proved to be completely unresectible. Patient was placed on high doses of chemotherapy both before and after surgery but it failed completely.

Patient had received phlorizin by bolus plus previously failed chemotherapy and lonidamine but responded only slowly. Therefore, he was switched to long term phlorizin over 12 to 24 hours with the same chemotherapy and heat regime and has responded to long infusions of phlorizin. The long infusion technique depleted the cell of glycogen and made it impossible for damage of cancer cell to be repaired. The results have been dramatic with marked response in weight gain, strength, well being. Tumor size has decreased significantly on direct palpation and CT scan. CT scan shows necroses of hepatic metastases.

All the examples above have been published in the following patent https://www.google.com/patents/US4840939

One of the inventor in the patent cited above was Dr. Harry H. LeVeen, a great man, former chief of surgery for 23 years at what is now the Veterans Affairs Medical Center in Brooklyn. There, in the 1970’s, he devised the LeVeen shunt, the first successful device for diverting fluids from the abdomen back into the bloodstream Ref

Mechanism

As discussed above, the anticancer effect of this component is due to the inhibition of Glut1, SGLT1 and SGLT2, transporters responsible for the transport of glucose inside the cells. As a result, is prohibiting glucose entry into the interior of the cell, impairs the vitality, metabolism, and repair and injury to cells caused by outside forces and changes sublethal cellular damage to lethal damage thus enhancing the effect of chemotherapy, radiation and heat.

Safety

Phlorizin is relatively non-toxic and has been administered to man parenterally and by mouth in wafer form. Doses as high as 15 grams have been administered in a single oral dose (J Clin Invest. 13:749, 1934). It has been given intravenously and subcutaneously to humans. Phlorizin by inhibiting glucose entry into the renal tubular cell causes glycosuria but since it also inhibits glucose entry into intestinal mucosal cells, absorption from the intestines is inhibited and sugar may be present in the feces. (Ref)

If for any reason it is necessary to interrupt the therapy, it can be counteracted with glucose infusions.

Preparation and administration

In rats, 10.4% of the ingested dose was recovered in urine after 24 h (Ref).

It should be used as IV since with oral therapy, much of the dose appears in the stool.

The dosage required to effectively inhibit cancer growth is easily determined since the patient acts as his own bioassay. The concentration which makes the tumor cells impermeable to glucose, makes other normal cells in the body also impermeable to glucose. When the dosage is adequate to prevent glucose entry into cells, the proximal tubular cells can no longer absorb glucose and glucosuria occurs. When total blocking of glucose absorption into the cell occurs, glucose then appears in the urine in almost the same concentration that it is present in the serum depending on the degree of water absorption of the urine. The correct dosage of the composition of the invention can be determined by measuring the glucose clearance, which approaches 125 cc’s per minute and which is the same as the xylose and inulin clearance. The creatinine clearance is a good substitute since it is only slightly higher than the inulin clearance.

Clinical experience has shown that, the composition of the invention is preferably administered in a continuous drip, approximately 1 mg per kilo of body weight per hour as a maintenance dose after total phlorizination to completely abolish glucose entry into cells. An initial loading dose of 4-6 mg per kilo of body weight is usually desirable to completely phlorizinize a patient as evidenced by the failure of the tubular cells to absorb glucose. This can be given by a slow push or over a ten minute interval. The duration of the effects last approximately one to one and one-half hours when administered intravenously as a single dose. With oral therapy, much of the dose appears in the stool. That glucose reabsorption in the kidney is completely blocked can be determined by comparing clearance of glucose to the clearance of xylose after administration.

Generally, it has been found that the administration of a total dosage of about 200-1000 mg of phlorizin or the indicated derivative per kilogram of body weight is an adequate dose in most patients. One need not fear giving an excessive quantity of phlorizin, however, since this substance has proven to be non-toxic and is rapidly excreted in the urine. The effect of phlorizin is dependent on a critical concentration in the extracellular fluid which will completely block all of the receptors sites for glucose.

The composition is generally administered during intervals of chemotherapy or radiation therapy by heating, radiation or chemotherapeutic drugs. Complete phlorizination for twenty-four hours prior to therapy reduces cellular glycogen levels and renders the therapy more effective. This dose is sufficient to reduce the blood glucose concentration to low levels and to partly or completely deplete cellular glucose. Further inhibition of glucose entry into the cancer cell is extended to the time of patient therapy by heat, chemotherapy or radiation and continued for 24 hours post therapy. The patient should be carefully observed for salt depletion. If for any reason it is necessary to interrupt the therapy, it can be counteracted with glucose infusions.

For I.V. infusion of phlorizin ten grams of phlorizin or the indicated analogs are dissolved in 20 ml of 95% ethyl alcohol which is then mixed with 930 ml of warm or hot 0.5 normal sodium chloride solution to which one ampule of sodium bicarbonate (50 mq in 50 ml H2 O) has been added. This mixture may require heating until it is warm enough to fully dissolve the phlorizin. After initial administering of the loading dose, the infusion is slowed to 10-15 ml per hour depending on body weight.

Summary of the above on preparation:

  1. phlorizin and not phloretin is preferred because of better water solubility of phlorizin
  2. Because of its poor oral absorption, the compositions of the invention is administered IV, dissolved in a suitable carrier such as 1/2 normal saline.
  3. 10g of phlorizin are dissolved in 20 ml of 95% ethyl alcohol (i.e. 50mg phlorizin/ml ethanol) which is then sterilized using a 0,22ug syringe filter  and than mixed with 930 ml of warm or hot 0.5 normal sodium chloride solution (1/2 normal saline) to which one ampule of sodium bicarbonate (50 mq in 50 ml H2 O) has been added. This means that every ml of nearly 1000ml solution will contain 10mg phlorizin.
    I am not sure if it i specifically required 0.5 normal saline or simply normal saline (i.e. 0.9%) is also fine.
  4. This mixture may require heating until it is warm enough to fully dissolve the phlorizin.

Summary of the above on administration:

  1. An initial loading dose of 4-6 mg per kilo of body weight is usually desirable to completely phlorizinize a patient. This can be given by a slow push or over a ten minute interval. (The duration of the effects last approximately one to one and one-half hours when administered intravenously as a single dose.)
    Note that according to the patent some patients receive a bolus loading dose of 2g or even 2.5g phlorizin, which for a person of about 65kg that is 30mg/kg, i.e. much higher than indicated above.
  2. Preferably, following the loading dose, the solution is further administered in a continuous drip, approximately 1-2 mg per kilo of body weight per hour as a maintenance dose for the next 8 to 24 hours (usually 8-12 hours). This means that for a 50kg person, 50mg-100mg phlorizin will be administrated every hour, i.e. about 5ml-10ml of the solution every hour
  3. During the above chemo or others treatments will be performed to increase their effectivness
  4. Note that upon prolonged exposure to aqueous solutions phlorizin hydrolyzes to phloretin and glucose. So if administrated for longer time maybe it would be better to produce new solution every few hours.

Update 16.01.2016: Prepared the solution as indicated above and it looks great for IV – very soluble in NaCl solution (did not used sodium bicarbonate)

Storage:

Powder at 4C; Solution at -20C for ax one month http://www.abcam.com/Phlorizin-ab143144.pdf

Source

CAS 60-81-1: Various chemical companies such as Cayman: http://www.caymaneurope.com/app/template/Product.vm/catalog/11576
Carbosynth: http://www.carbosynth.com/carbosynth/website.nsf/(w-productdisplay)/56CD657845777A2D802573EB0072A5C9
I am nut sure if this source can be trusted but the claim is >95% at low cost: https://www.badmonkeybotanicals.com/organic-apple-root-phloridzin-extract

References

In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter http://onlinelibrary.wiley.com/doi/10.1002/ijc.24189/full

Phloretin (Ph), a natural product found in apples and pears with glucose transporter (GLUT) inhibitory activity, exerts antitumor effects. However, little is known about its effects on human liver cancer. The purpose of this study is to test the cytotoxic effects of Ph on HepG2 cells and to identify the underlying molecular pathways. Human hepatocellular carcinoma specimens and HepG2 show a high level of GLUT2 transporter activity in the cell membrane. Real-time PCR and MTT assays demonstrate that Ph-induced cytotoxicity correlates with the expression of GLUT2. Flow cytometry and DNA fragmentation studies show that 200 μM Ph induces apoptosis in HepG2, which was reversed by glucose pretreatment. GLUT2 siRNA knockdown induced HepG2 apoptosis, which was not reversed by glucose. Western blot analysis demonstrates that both intrinsic and extrinsic apoptotic pathways in addition to Akt and Bcl-2 family signaling pathways are involved in Ph-induced cell death in HepG2 cells. Furthermore, using flow cytometry analysis, a mitochondrial membrane potential assay and Western blot analysis, we show that cytochalasin B, a glucose transport inhibitor, enhances the Ph-induced apoptotic effect on HepG2 cells, which was reversed by pretreatment with glucose. Furthermore, we found significant antitumor effects in vivo by administering Ph at 10 mg/kg intraperitoneally to severe combined immune deficiency mice carrying a HepG2 xenograft. A microPET study in the HepG2 tumor-bearing mice showed a 10-fold decrease in 18F-FDG uptake in Ph-treated tumors compared to controls. Taken together, these results suggest that Ph-induced apoptosis in HepG2 cells involves inhibition of GLUT2 glucose transport mechanisms.

Treatment of cancer with phlorizin and its derivatives https://www.google.com/patents/US4840939

Malignant, neoplastic cells are treated by inhibiting glucose transport into the cell by administering phlorizin, phloretin or its analogs while concurrently administering adjunct therapy such as heat, radiation or chemotherapy. In this manner, the cells are prevented from growing or repairing the damage caused by the adjunct therapy, which can be administered in dosages that would otherwise be non-lethal if used alone.

SGLT Inhibitors as New Therapeutic Tools in the Treatment of Diabetes http://iqanda-cme.com/assets/pdf/Kinne.pdf

Recently, the idea has been developed to lower blood glucose levels in diabetes by inhibiting sugar reabsorption in the kidney. The main target is thereby the early proximal tubule where secondary active transport of the sugar is mediated by the sodium-D-glucose cotransporter SGLT2. A model substance for the inhibitors is the O-glucoside phlorizin which inhibits transport competitively. Its binding to the transporter involves at least two different domains: an aglucone binding site at the transporter surface, involving extramembranous loops, and the sugar binding/ translocation site buried in a hydrophilic pocket of the transporter. The properties of these binding sites differ between SGLT2 and SGLT1, which mediates sugar absorption in the intestine. Various O-, C-, N- and S-glucosides have been synthesized with high affinity and high specificity for SGLT2. Some of these glucosides are in clinical trials and have been proven to successfully increase urinary glucose excretion and to decrease blood sugar levels without the danger of hypoglycaemia during fasting in type 2 diabetes.

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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