Publication de Nicole Delepine : Tolerance of oral lipoid acid and hydroxycitrate combination in cancer patients : first approach

Nicole delépine, le site officiel English Version Version Française
Accueil Site officiel ACCUEIL
Accueil du site officiel de Nicole Delepine
publication cancérologue réputé nicole delepine ostéosarcome
sarcome ewing publications du docteur nicole delepine
Publié sur : congrès de l'AACR (American Association for Cancer Research) - Chicago USA - 2012
Voir la version PDF de cette publication : Document PDF
Tolerance of oral lipoid acid and hydroxycitrate combination in cancer patients : first approach
H. Cornille, S. Alkhallaf, L. Schwartz, GF. Baronzio, Nicole Delépine

Tolerance of oral lipoid acid and hydroxycitrate combination in cancer patients : first approach



The metabolic alterations of cancer


metabolic alteration of cancer


Cancer Metabolism: A Recurrent Approach



Preclinical evidences:
1925 - In most cancer cells: high aerobic glycolysis and lactic acid secretion. Warburg, Nobel Prize.
1997 - Oncogenes and tumor suppressor genes alter metabolic pathways. Shim H. PNAS.
2002 - Mutated forms of metabolic enzymes could promote cancer. Tomlinson I. Nat. Genet.
2009 - Cell chronic exposure to insulin and glucose favors transformation. Schwartz & Demidem, AACR.

Clinical evidences:
2009 - Metformin long term treatment of diabetes reduced cancer incidence. Libby G. Diabetes Care.
2010 - Obesity is the second risk factor for cancer. Khan N. Cancer Lett.
2010 - Use of an indirect PDH activator: regression of glioblastoma in 3/5 patients. Michelakis E. Sci Transl Med.

Chemotherapy alters cell methylation


Chemotherapy alters cell methylation


Cancer is a metabolic disease


Cancer is a metabolic disease


Metabolic Pathways Activated in Cancer


Metabolic Pathways Activated in Cancer

Metabolic Pathways Activated in Cancer


Links between oncogenes and metabolism


Links between oncogenes and metabolism


Around one hundred identified targets


Links between oncogenes and metabolism


Selected drugs for in vivo screening


Selected drugs for in vivo screening


Selection Process


Selection Process


In vivo drug combination tests


Subcutaneous inoculation of tumor cells (~3000 mice)
3 syngeneic models:
Lung carcinoma (LLC),
Bladder carcinoma (MBT-2),
Melanoma (B16-F10)

Treatment via intraperitoneal administration of the drugs.

Tumor development follow-up:
Tumor volume (caliber, twice a week)
Animal weight
Survival

ALA/ HCA Efficacy


ALA/ HCA Efficacy

The ALA/ HCA combination doubles survival as compared to untreated mice.

ALA/ HCA combined with chemotherapy


ALA/ HCA combined with chemotherapy

Addition of ALA/ HCA to chemotherapy significantly enhances survival.

ALA/HCA Efficacy


ALA/HCA Efficacy

The combination significantly reduces tumor development (equivalent to cisplatin chemotherapy).

Animal models main results


Combination : Alpha lipoic acid + Hydroxycitrate
Results : Slows down tumor development, extends survival
Efficiency : Similar to chemotherapy, Potentiates CHT effectiveness
Models : Syngeneic mouse models: melanoma, bladder and lung carcinoma mice cells

Our previous publications


Tend to demonstrate that lipoïc acid (ALA) and hydroxycitrate (HCA) combination decreases.
The tumor growth in mice with either lung cancer, bladder cancer or melanoma.

Lipoic acid


ALA, well known treatment of the diabetic neuropathy its interest in cancer is growing
ALA is a cofactor in mitochondrial energy metabolism and a potent regulator of the cell's redox status with effects on P13K and AMPK signaling and related transcriptional pathways.
These mechanisms increase its interest in cancer and aging relative diseases.

Alpha-Lipoic acid (LA; 5-(1,2-dithiolan-3-yl) pentanoic acid) was originally isolated from bovine liver by Reed in 1951.
LA was once considered a vitamin. Subsequently, it was found that LA is not a vitamin and is synthesized by plants and animals.
LA functions as a cofactor for mitochondrial enzymes by catalyzing the oxidative decarboxylation of pyruvate, alpha-ketoglutarate and branched-chain alpha-keto acids.
Dihydrolipoic acid (DHLA) is the reduced form of LA.

Alpha-Lipoic acid (LA; 5-(1,2-dithiolan-3-yl) pentanoic acid and its reduced form dihydrolipoic acid (DHLA)


Alpha-Lipoic acid


Alpha lipoic acid (ALA)


Mechanism of action :
-Anticancer activity via its activation of Pyruvate dehydrogenase (PDH)
-Other know activities: antioxidant and cofactor of several enzymes (Biewenga 1997)

Actual approved treatment for :
- Diabetic neuropathy and neurodegeneration (Thioctacid, MEDA Pharma in Germany),
- Dietary supplement in many countries (EU, USA, ...)

Anticancer activity:
- In vitro in the µM range (apoptosis induction, about 100 publications from end of 1990s and 2000s and Biorébus data)
- Low tumor inhibition in mice (20mg/kg/day) (Biorébus, no other publication)

In human, few articles:
- Reduction of oxidative stress caused by anticancer agents
(Mantovani G. Onc. Rep. 2002, Nutrition 2008)
- ALA and Low-dose Naltrexone prolonged the survival of three cancer patients (pancreas); one case: > 78months (Berkson B. 2006, 2009)

Very Good Tolerance (Cremer D. 2006) :
- No Secondary Effects at 1200mg/day during 2 years
- No Mutagenic or Genotoxic Activity
- Bioavailability: after 600mg oral dose of Na-RALA, Cmax = 70µM (Carlson D. 2007)

Therapeutic action of LA and DHLA


Their therapeutic action is based on their antioxidant properties: they meet all the criteria for an ideal antioxidant because they can easily quench radicals, can chelate metals, have an amphiphilic character.

They interact with other antioxidants and can regenerate them. For this reason, LA is called an antioxidant of antioxidants.

Current studies support the use of LA in the ancillary treatment of many diseases, such as diabetes, cardiovascular, neurodegenerative, autoimmune diseases, cancer and AIDS. LA and DHLA do not exhibit any serious side effects.

Hydroxycitrate (HCA)


Mechanism of action: ATP Citrate Lyase Inhibitor (only identified target) (Lowenstein 1969)
Extracted from Garcinia cambodgia fruit rinds, an indian traditional condiment
Indication: nutritional supplement for weight loss (for instance Slimax Solgar)

Anticancer Activity:
- In vitro about 100µM (2 publications and Biorébus data) (Board 1996, Beckner 2010)
- Moderate tumor inhibition in mice (500mg/kg/day) (Biorébus, no other publication)
- In human, no known anticancer application of HCA (few articles for whole garcinia extracts)

Very Good Tolerance (Soni MG 2004):
- No Secondary Effects at 5g/day during 8 weeks
- No Mutagenic or Genotoxic Activity

Bioavailability: after 2g oral dose of Ca/K HCA, Cmax = 16µM (Loe Y. 2001)

Potential role of hydroxycitrate ?


This could also be a way to inhibit tumor cells growth as other evoked mechanisms :
- increase of serotonin in the brain.
- inhibition of pancreatic alpha amylase and intestinal alpha glucosidase.
- leading to a reduction in carbohydrate metabolism.

Lipoic acid and hydroxycitrate


both molecules target the abnormal metabolic pathways such as seen in cancer
There combination appears in mice to be more effective than their use alone


We report here the early clinical tolerance evaluation of a daily metabolic combination in humans associated with chemotherapy.

Italian experience :
median duration of 14,5 months (4 to 20 m)


4 p. : 3 F, 1 M , median age 57 y( 37 - 81 y)
1 breast cancer
1 nasopharyngeal carcinoma
1 pancreatic adenocarcinoma
1 glioblastoma.
Doses : ALA 1,2 g/d HCA 1,2 g/d orally
All but one p. had concomitant chemotherapy

French experience :
Jan 08 to Nov 11


13 p. with local relapse and/or metastatic cancer with a combination of ALA -HCA
7 M, 6 F, median age 45 y (28 -74 )
2 colon, 1 lung , 1 hepatocarcinoma, 5 sarcomas, 1 neuro-endocrine
HCA administered orally , 3 g / d (1 g x3/d) from Oct 11 increased to 6 g /d for 3 last 6 p.
ALA 1,8 g /d ( 600 m g x3/d)
Median duration : 3 months (15 d - 5 m, 1 p. 20 m)

Results:


This association was well tolerated with few clinical disturbances :
- vomiting , nausea
- 5 patients had a gastric protective treatment
- 2 because of corticotherapy
- The increased dose of ALA was well tolerated
- No hepatic toxicity found
- no weight loss ,no hypoglycemia

Inconveniences :


Bad and discontinued observance for patients in relation with the cost of these medicines.
The difficulty to buy them (only by online pharmacy for ALA in France)
The tolerance of HCA was mild because of gastric pain but patients continue the treatment.

Availability of the drugs :


Alpha-lipoic acid : 13 companies having marketing authorization for iv formulation against diabetic neuropathy in Germany.
(Wörwag Pharma, Stadapharm, AAA-Pharma, MIP Pharma, CNP Pharma, Berlin-Chemie, Biomo Pharma, Esparma, Ratiopharm, Mit Gesundheit, Hexal AG, MEDA Pharma, Trommsdorff).

Hydroxycitrate : Garcinia cambodgie extract freely available :
In France, as a food supplement: Slimax® from Solgar (Pharmacy and health food stores)
In USA, as a food supplement and diet beverage ingredient: Super Citrimax® from Interhealth

Conclusion:


Combination of safe drugs may be able to:
- Reduce tumor development rate
- Enhance survival
- Improve chemotherapy efficacy

ALA / HCA : a new adjuvant to chemotherapy ?
ALA - HCA combination well tolerated promising treatment in cancer patients.
The switch to IV ALA would permit to obtain higher blood peaks and better observance
Nevertheless we don't know which dosage would be the best for patients
Randomized clinical trials are necessary to evaluate the efficacy on tumor progression in correlation with pharmacologic studies.




publications médicales


sarcome d'ewing
nicole delepine cancer tumeur ostéosarcome
Facebook Tweeter Google+