The Long-Term Survival of a Patient With Stage IV Renal Cell Carcinoma Following an Integrative Treatment Approach Including the Intravenous α-Lipoic Acid/Low-Dose Naltrexone Protocol

First Published December 19, 2017 

The first key component in the patient’s treatment protocol was lipoic acid (ALA). IV ALA can reach much higher plasma levels than the oral form, with the oral capsules maintaining levels in between IV infusions. ALA has multiple activities; for instance, it is a powerful antioxidant and heavy metal chelator.⁹ It appears that 3 of its actions are relevant in this case: its anti-inflammatory activity, the effect on mitochondrial metabolism, and its epigenetic activity.

First, ALA may discourage the growth of cancer cells by its action involving the pro-inflammatory transcription factor, nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB).¹⁰

Unmitigated NF-κB activation can produce proliferation, angiogenesis, mutagenesis, metastasis, and chemo-radio resistance in malignant cells and leave them resistant to apoptosis.¹¹ Patients with advanced cancer exhibit greatly elevated markers of oxidative stress and an unrelenting inflammatory process in part due to NF-κB activation.¹¹ ALA inhibits NF-κB, blunting these deleterious effects and discouraging the unbridled growth of cancer cells.

Another significant interaction of ALA is with the pyruvate dehydrogenase enzyme complex (PDHC) and its regulatory enzyme pyruvate dehydrogenase kinase (PDK). PDHC consists of 3 mitochondrial enzymes that sit in the intersection of cytoplasm and mitochondria, glycolysis and the Krebs cycle, and anaerobic and aerobic energy metabolism. PDHC converts cytoplasm-generated pyruvate into acetyl CoA, which then enters the Krebs cycle. ALA is the necessary cofactor for PDHC, and without ALA there is no energy produced in the mitochondria.

PDK phosphorylates and inhibits PDHC, regulating its activity. ALA inhibits PDK, and by doing so it further increases PDHC activity.^12,13

These enzymes are involved in a metabolic peculiarity of cancer cells, the so-called Warburg effect, also called “aerobic glycolysis,” a phenotype rather common to malignancies: cancer cells preferentially metabolize glucose and pyruvate into lactic acid, even in the presence of oxygen.¹⁴ This increase in glycolysis might favor the formation of amino acid and nucleotide precursors, important for a rapidly proliferating cell, whose importance might offset the disadvantage of a reduced ATP production.^15,16

McFate et al¹⁷ have shown that inhibition of PDHC activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. This inhibition occurred by an enhanced expression of pyruvate dehydrogenase kinase (PDHK). Knockdown of PDHK restored pyruvate dehydrogenase (PDH) activity, reverted the Warburg metabolic phenotype, decreased invasiveness, and inhibited xenograft tumor growth in nude mice.

Clear cell RCC is characterized by the constitutive upregulation of the hypoxia inducible factor-1.¹⁸ Hypoxia inducible factor-1 has been shown to promote the Warburg effect in several cancers, including clear cell RCC,¹⁸ in part due to the activation of PDHK (one of its target genes¹⁹), and subsequent inhibition of PDH. Recently, Lim et al²⁰ demonstrated that in this type of cancer, most of the 10 tumor samples studied had an elevated PDHK enzyme level, and a decreased PDHC activity, when compared with patient-matched normal tissue.

Schell et al²¹ furthered this idea by implying that the inhibition of the Warburg effect in colon cancer cells was associated with decreased cancer cell xenograft growth in nude mice.

Studying a related issue concerning these enzymes, Kaplon et al²² demonstrated that PDH is a crucial mediator of malignant cell senescence induced by BRAF^V600E, a protein kinase and oncogene that is often mutated in melanoma and other cancers. This BRAF^V600E-induced senescence was accompanied by simultaneous inhibition of PDHK. Enforced normalization of PDHK inhibited PDH and abolished oncogene-induced senescence, thereby allowing BRAF^V600E-driven melanoma growth.

Since ALA inhibits PDHK and activates PDHC, the metabolic peculiarity of cancer cells described by Warburg may be mitigated, and it is likely that the overall cancer growth program may be altered. It is also possible, according to Kaplon’s work, that tumor cell senescence may also be promoted by ALA’s action on these enzymes.

Another potential antineoplastic action of ALA concerns its epigenetic activity. ALA can inhibit histone deacetylase (HDAC) activity in human tumor cells.^23,24 Histone acetylation and deacetylation are important components in gene regulation.

An active avenue of cancer research involves inhibitors of HDACs, with drugs such as vorinostat.

Recently, it has been found that PDH, thought to be an exclusive mitochondrial enzyme, is also present and functional in the nucleus, probably translocated from the mitochondrion.²⁵ Inhibition of nuclear PDH in isolated nuclei decreased the acetylation of histone lysine residues. This nuclear PDH has also lipoic acid as cofactor, so ALA provides a source for nuclear acetyl-CoA synthesis required for histone acetylation and epigenetic regulation.

These epigenetic modifications give ALA the capacity of influencing, at a genetic level, tumor behavior and growth. In other words, cancer is not only a genetic disease but is also a metabolic disease. ALA seems to address both of these components.

IV vitamin C was also part of the patient’s treatment protocol. Integrative medical doctors have administered this agent for many years with some positive case history reports. Some of these results include reversal of pulmonary metastases from RCC and from hepatocellular carcinoma.^26,27

HCA is an extract from the citrus fruit, Garcinia cambogia. Not only it inhibits pancreatic α-amylase and intestinal α-glucosidase, but also inhibits ATP-citrate lyase,²⁸ a cytoplasmic enzyme that catalyzes the generation of acetyl-CoA from mitochondrial-generated citrate.²⁹ Acetyl-CoA is a vital building block for the endogenous biosynthesis of fatty acids, cholesterol, and isoprenoids.