Archive for the ‘Alpha Lipoic Acid’ Category

Alpha Lipoic Acid and Frataxin: A New Indication for an Old Antioxidant?

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Posted 15 Jun 2011 — by James Street
Category Alpha Lipoic Acid, Alpha Lipoic Acid, antioxidants, Chemotherapy, Cisplatin, docetaxel, Drug Resistance
Alpha Lipoic Acid and Frataxin: A New Indication for an Old Antioxidant?
James W. Russell
James W. Russell, Department of Neurology, University of Maryland School of Medicine & Maryland VA Medical Center, Baltimore, MD 21201, USA;

Correspondence: James W. Russell, M.D., M.S., Department of Neurology, University of Maryland, School of Medicine, 22 South Greene Street, Box 175, Baltimore, MD 21201-1595, Tel:             410-706-6689 begin_of_the_skype_highlighting 410-706-6689 end_of_the_skype_highlighting ; Fax: 410-706-4949 begin_of_the_skype_highlighting 410-706-4949 end_of_the_skype_highlighting, E-mail: JRussell@som.umaryland.edu

Cisplatin is an effective treatment for breast, ovarian, testicular, and small cell lung malignancies, however its use leads to a dose-limiting and cumulative sensory neuronopathy. The effects of cisplatin neurotoxicity can persist for decades (Strumberg et al., 2002). The mechanism of cisplatin toxicity is uncertain, although it has been shown in vitro to reduce fast axonal transport, and induces apoptosis in dorsal root ganglion cells (DRG) by forming high affinity adducts between cisplatin and either genomic or mitochondrial DNA (McDonald et al., 2005; Peltier and Russell 2002). Adduct formation is associated with translocation of the proapoptotic protein Bax to the mitochondrion and release of cytochrome c into the cytosol. This series of events leads to a fas receptor-independent form of programmed cell death (McDonald and Windebank 2002). Cisplatin is frequently administered in combination with paclitaxel and the effect of combination therapy has recently been tested in an animal model (Carozzi et al., 2009). Current data are insufficient to conclude if any tested neuroprotective agents, for example amifostine, diethyldithiocarbamate, glutathione, Org 2766, or Vitamin E prevent or reduce the neurotoxicity of platin drugs (Albers et al., 2007).

Dr. Melli and colleagues in “Alpha-lipoic Acid Prevents Mitochondrial Damage and Neurotoxicity in Experimental Chemotherapy Neuropathy” present an intriguing new mechanism for cisplatin neuronal injury. Using an embryonic day (E-15) DRG culture system, neurons exposed to cisplatin showed a significant reduction in frataxin expression (Melli et al., 2008). Human frataxin is a ~17kDa protein whose deficiency has been associated with Friedreich’s ataxia. Friedreich’s ataxia is a progressive neurodegenerative disease that affects both central and peripheral axons. However, like cisplatin neuropathy, Friedreich’s ataxia is associated with significant degeneration of DRG sensory neurons. Frataxin is intimately associated with several aspects of intracellular iron metabolism and detoxification including iron binding/storage and iron chaperone activity (Campanella et al., 2009). Frataxin also interacts with the electron transport chain proteins, activates glutathione peroxidase, and increases the mitochondrial membrane potential. Frataxin deficiency is associated with a severe deficiency in mitochondrial DNA, an event that results in reduced oxidative phosphorylation and altered antioxidant defenses. Furthermore, a major consequence of the severe depletion of mitochondrial DNA would be mitochondrial bioenergetic failure in the peripheral nervous system (Koch and Britton 2008).
Another observation in the present study is the formation of autophagosomes in DRG treated with cisplatin. Typical double membrane bound vacuoles containing degenerative mitochondria were observed in DRG neurons. Autophagy is an important process involved in the degradation of cytoplasmic organelles and in particular mitochondria. Recent research shows that autophagosomes form on the surface of the mitochondria and they then peel off from mitochondria. Autophagic programmed cell death (type II) is characterized by the accumulation of autophagic vesicles (autophagosomes and autophagolysosomes) and is often observed when massive cell elimination is demanded or when phagocytes do not have easy access to the dying cells (Shintani and Klionsky 2004). It is unclear if autophagy causes neuronal or axonal pathology or is a result of the injury. However despite this uncertainty, the current observations by Melli and colleagues provide a rational explanation for the pathophysiological changes that occur in cisplatin neuropathy.
In the present study, paclitaxel reduced the number of functioning mitochondria in DRG neurons and Schwann cells, induced apoptosis in both cells, and impaired neurite growth. Paclitaxel is a common adjunctive therapy in women with node positive breast cancer. It is frequently used in combination with cisplatin and other chemotherapeutic drugs and is also used for other solid tumors such as ovarian and non-small cell lung cancer. A length-dependent sensorimotor axonal neuropathy is a common dose-dependent side effect of treatment. It can also rarely cause cranial neuropathies, motor involvement and autonomic dysfunction (Peltier and Russell 2006). Paclitaxel binds to tubulin and hyperstabilizes microtubules thus promoting the assembly and reducing the disassembly of microtubules in unmyelinated and myelinated axons. These changes reduce normal axonal transport. Several potential therapies have been assessed in taxol-induced neuropathy including glutamine and calpain inhibitors (Peltier and Russell 2006). However, these potential neuroprotective therapies have not been tested in large randomized clinical trials.
An important observation in the study by Melli et al is the finding that alpha-lipoic acid (α-lipoic acid) prevented mitochondrial damage and that this was dependent on expression of frataxin. α-lipoic acid had neuroprotective effects with both cisplatin and paclitaxel toxicity in cell culture. In contrast to the data with cisplatin, the effect of α-lipoic acid on paclitaxel induced apoptosis was less significant, which is not surprising as apoptosis is not the main toxic mechanism of paclitaxel. In DRG cultures transfected with anti-frataxin siRNA, there was reduced axonal outgrowth. Cisplatin and paclitaxel showed increased neurotoxicity in frataxin knockdown cultures and α-lipoic acid did not prevent the axonal damage as it did in non-transfected cultures. In contrast, α-lipoic acid increased the expression of frataxin in sensory neurons. A further observation was that whereas cisplatin significantly reduces the expression of frataxin, paclitaxel does not. This is despite an increased neurotoxicity in the anti-frataxin siRNA cultures. The implication of this is not clear. Importantly, the α-lipoic acid had to be administered prior to exposure to cisplatin or paclitaxel in order to prevent neurotoxicity. It should be clearly noted that these are cell culture studies and may not be clinically relevant. However, α-lipoic acid has been shown in a small study to improve neuropathy when used post docetaxel/cisplatin treatment in subjects who had already developed peripheral neuropathy (Gedlicka et al., 2003). Patients were treated with 600 mg intravenous α-lipoic acid once a week for 3–5 weeks followed by 1800 mg orally daily for up to 6 months. These results will need to be confirmed in a larger randomized controlled study.
α-lipoic acid is one of the most extensively studied antioxidants. Oxidative stress has been associated with several types of neuropathy including diabetic and chemotherapy-induced neuropathy (Russell and Kaminsky 2005). In the peripheral nerve, α-lipoic acid reduces oxidative stress and the generation of peroxinitrites, inhibits activation of caspases, and improves peripheral nerve endoneurial blood flow. α-lipoic acid in vivo is reduced to active dihydrolipoate and is able to regenerate other antioxidants such as vitamin C, vitamin E, and reduced glutathione through redox cycling. The antioxidant potential of α-lipoic acid has been used to treat several neurological diseases including multiple sclerosis and stroke. However, it has been used most extensively for the treatment of neuropathy, and in particular in diabetic neuropathy. Most experimental diabetic neuropathy studies have shown variable degrees of improvement with α-lipoic acid treatment. Clinical trials have shown mixed results. However, in one of the larger, multicenter, randomized, double-blind, placebo-controlled studies of diabetic neuropathy, there was a small but significant improvement in the neuropathy symptom score but not in other endpoint measures (Ziegler et al., 1999). In general, short term treatment with α-lipoic acid mildly improves both neuropathic symptoms and deficits and the treatment has relatively few side effects.
The observation that α-lipoic acid prevents neuronal and Schwann cell injury in an experimental cell culture model of cisplatin and paclitaxel-induced toxicity and that this is dependent on levels of frataxin, is a novel finding. It remains to be seen whether these observations will prove to be true in toxic neuropathy in humans and if α-lipoic acid will prevent this neurotoxicity. Further basic science studies to examine alternative mechanism/s of action of α-lipoic acid in chemotherapy-induced neuropathy and more robust clinical trials with α-lipoic acid are needed.
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References
  • Albers J, Chaudhry V, Cavaletti G, Donehower R. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2007:CD005228. [PubMed]
  • Campanella A, Rovelli E, Santambrogio P, Cozzi A, Taroni F, Levi S. Mitochondrial ferritin limits oxidative damage regulating mitochondrial iron availability: hypothesis for a protective role in Friedreich ataxia. Hum Mol Genet. 2009;18:1–11. [PubMed]
  • Carozzi V, Chiorazzi A, Canta A, Oggioni N, Gilardini A, Rodriguez-Menendez V, Avezza F, Crippa L, Ceresa C, Nicolini G, Bossi M, Cavaletti G. Effect of the chronic combined administration of cisplatin and paclitaxel in a rat model of peripheral neurotoxicity. Eur J Cancer. 2009;45:656–665. [PubMed]
  • Gedlicka C, Kornek GV, Schmid K, Scheithauer W. Amelioration of docetaxel/cisplatin induced polyneuropathy by alpha-lipoic acid. Ann Oncol. 2003;14:339–340. [PubMed]
  • Koch LG, Britton SL. Aerobic metabolism underlies complexity and capacity. J Physiol. 2008;586:83–95. [PMC free article] [PubMed]
  • McDonald ES, Randon KR, Knight A, Windebank AJ. Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: a potential mechanism for neurotoxicity. Neurobiol Dis. 2005;18:305–313. [PubMed]
  • McDonald ES, Windebank AJ. Cisplatin-Induced Apoptosis of DRG Neurons Involves Bax Redistribution and Cytochrome c Release But Not fas Receptor Signaling. Neurobiol Dis. 2002;9:220–233. [PubMed]
  • Melli G, Taiana M, Camozzi F, Triolo D, Podini P, Quattrini A, Taroni F, Lauria G. Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Exp Neurol. 2008;214:276–284. [PubMed]
  • Peltier AC, Russell JW. Recent advances in drug-induced neuropathies. Curr Opin Neurol. 2002;15:633–638. [PubMed]
  • Peltier AC, Russell JW. Advances in understanding drug-induced neuropathies. Drug Saf. 2006;29:23–30. [PubMed]
  • Russell JW, Kaminsky AJ. Oxidative injury in diabetic neuropathy. In: Opara E, editor. Nutrition and Diabetes: Pathophysiology and Management. Taylor & Francis; Boca Raton: 2005. pp. 381–397.
  • Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science. 2004;306:990–995. [PMC free article] [PubMed]
  • Strumberg D, Brugge S, Korn MW, Koeppen S, Ranft J, Scheiber G, Reiners C, Mockel C, Seeber S, Scheulen ME. Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol. 2002;13:229–236. [PubMed]
  • Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schutte K, Kerum G, Malessa R. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999;22:1296–1301. [PubMed]

Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy

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Posted 15 Jun 2011 — by James Street
Category Alpha Lipoic Acid, Chemotherapy, Cisplatin, docetaxel, Neuropathy

Giorgia Mellia, Corresponding Author Contact Information, E-mail The Corresponding Author, Michela Taianaa, Francesca Camozzia, Daniela Trioloc, Paola Podinic, Angelo Quattrinic, Franco Taronib and Giuseppe Lauriaa

aNeuromuscular Diseases Unit, IRCCS Foundation Neurological Institute “Carlo Besta”, Via Celoria, 11 20133, Milan, Italy

bBiochemistry and Genetics Units, IRCCS Foundation Neurological Institute “Carlo Besta”, Milan, Italy

cSan Raffaele Vita e Salute University, Milan, Italy

Received 27 June 2008;
revised 8 August 2008;
accepted 21 August 2008.
Available online 9 September 2008.

 

Abstract

The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection.

We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. Our results demonstrate that both cisplatin and paclitaxel cause early mitochondrial impairment with loss of membrane potential and induction of autophagic vacuoles in neurons. Alpha-lipoic acid exerts neuroprotective effects against chemotherapy induced neurotoxicity in sensory neurons: it rescues the mitochondrial toxicity and induces the expression of frataxin, an essential mitochondrial protein with anti-oxidant and chaperone properties. In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.

Keywords: Neurotoxicity; Mitochondria; Chemotherapy; Alpha-lipoic acid; Frataxin

Article Outline

Introduction
Materials and methods
Neuronal cells and Schwann cells cultures
Neuroprotection assay: axonal outgrowth measurement
Neuroprotection assay: neuronal apoptosis
Mitochondrial function assay
Mitochondrial membrane potential changes assay
Electron microscope analysis
Real-time PCR assay
Small interfering RNA experiments
Results
Alpha-lipoic acid protect sensory neurons against paclitaxel and cisplatin induced axonal damage and apoptosis
Paclitaxel and cisplatin neurotoxicity is associated with a reduction of functioning mitochondria in DRG cultures
Alpha-lipoic acid prevents the early loss of membrane potential differential in mitochondria exposed to paclitaxel and cisplatin
Alpha-lipoic acid rescues mitochondrial morphological abnormalities induced by paclitaxel and cisplatin
Alpha-lipoic acid induces frataxin expression in sensory neurons
Discussion
Acknowledgements
References

Amelioration of docetaxel/cisplatin induced polyneuropathy by α-lipoic acid

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Posted 15 Jun 2011 — by James Street
Category Alpha Lipoic Acid, docetaxel, Docetaxel (deoxycytidine drug)
  1. C. Gedlicka,
  2. G. V. Kornek,
  3. K. Schmid and
  4. W. Scheithauer*

+ Author Affiliations


  1. Clinical Division of Oncology, Department of Internal Medicine I, University of Vienna, Vienna, Austria
  1. *E-mail: werner.scheithauer@akh-wien.ac.at

Docetaxel (Taxotere®; Aventis, Strasbourg, France) is currently considered to be one of the most important anticancer drugs. It is a semi-synthetic agent derived from baccatin III extracted from renewable Taxus baccata needles, which binds to tubulin inducing its polymerization [1]. It inhibits cell replication and leads to apoptosis. Docetaxel has displayed significant antitumor activity against non-small-cell lung cancer (NSCLC), head and neck tumors and breast cancer [2].

Apart from myelosuppression (neutropenia), hypersensitivity reactions and fluid retention, one significant adverse reaction associated with the use of docetaxel is a cumulative and predominantly sensory neurotoxicity [2]. When combined with other neurotoxic agents, such as cisplatin, this adverse reaction may become dose-limiting. Taxane-induced neuropathy tends to occur early during therapy with amelioration after discontinuation of therapy; whereas, cisplatin-induced neuropathy tends to develop after a critical cumulative dose and frequently worsens during the first months following therapy discontinuation [3].

Alpha-lipoic acid (Thioctacid®; Asta Medica, Frankfurt, Germany), which has been shown to be effective in both the somatic and the autonomic neuropathies in diabetes, normalizes the endoneural bloodflow [4], reduces oxidative stress [5, 6] and improves vascular dysfunction [7]. In a placebo-controlled trial in patients with diabetic neuropathy, a significant relief of neuropathic symptoms was observed in patients who received α-lipoic acid [8].

We investigated the therapeutic potential of α-lipoic acid to counteract docetaxel plus cisplatin related peripheral neuropathy (PNP) in patients with advanced gastric cancer (n = 5), NSCLC (n = 6), and head and neck tumor (n = 3).

From October 2000 to March 2001 a total of 14 patients who received docetaxel 50 mg/m2 in combination with cisplatin 50 mg/m2 every 2 weeks, experienced at least one symptom of paresthesia, dysesthesia or pain, including a burning sensation, thus fulfilling the criteria of polyneuropathy [9]. Their pretreatment characteristics are summarized in Table 1. Neurological symptoms were serially evaluated in all patients before each cytotoxic drug administration according to the World Health Organization (WHO) grading system, which has been developed to assess the neurotoxicity occurring during treatment with potentially neurotoxic agents [9]. All patients who experienced PNP grade 2 (severe paresthesia and/or mild weakness) or grade 3 (intractable paresthesia and/or marked motor loss) during or after docetaxel/cisplatin combination chemotherapy received α-lipoic acid. The treatment regimen consisted of α-lipoic acid 600 mg i.v. once a week for 3–5 weeks followed by 1800 mg td p.o. until full recovery from neurological symptoms for a maximum of 6 months. After a median of eight chemotherapy courses (range 6–12) and a median cumulative docetaxel dose of 400 mg/m2 (range 300–600 mg/m2) a total of 14 patients suffered from PNP grade 2 (10 patients) or 3 (four patients).

Table 1.

Patient characteristics

Treatment with α-lipoic acid resulted in an improvement in neurological symptoms (by ≥1 WHO toxicity score) in six patients with grade 2, and two patients who suffered from grade 3 PNP. The median time to response was 4 weeks (range 3–12 weeks) and the median duration of treatment with α-lipoic acid was 2 months (range 1–4 months). Six patients did not respond, two of them initially presented with PNP grade 3, and four had PNP grade 2. Apart from moderate gastric pain in two patients and WHO grade 1 and 2 nausea in one patient each, α-lipoic acid did not cause any other adverse reactions.

Our data suggest that α-lipoic acid administered in the current schedule was able to counteract docetaxel-related PNP. Despite other supportive therapies (such as amifostin, calcium/magnesium infusion, sodium channel blockers and gabapentin), further investigation of α-lipoic acid in the treatment of docetaxel ± cisplatin-related polyneuropathy seems warranted.

C. Gedlicka, G. V. Kornek, K. Schmid & W. Scheithauer*

Clinical Division of Oncology, Department of Internal Medicine I, University of Vienna, Vienna, Austria (*E-mail: werner.scheithauer@akh-wien.ac.at)

References

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    Low PA, Nickander KK, Tritschler H. The roles of oxidative stress and of antioxidant treatment in experimental diabetic polyneuropathy. Diabetes1997; 46 (Suppl 2): 38–42.
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    Morcos M, Borcea V, Isermann B et al. Effect of the antioxidant lipoic acid on the progression of endothelial cell damage and albuminuria in patient with diabetes mellitus. Diabetes Res Clin Pract2001; 52: 175–183.
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    Ziegler D, Hanefeld MH, Ruhnau KJ et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant α-lipoic acid. A 7-month multicenter randomized controlled trial (ALADIN III Study). Diabetes Care1999; 22: 1296–1301.
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    Postma TJ, Heimans JJ. Grading of chemotherapy-induced peripheral neuropathy. Ann Oncol2000; 11: 509–513.