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due to the upregulation of nerve growth factor. In cancer Alpha-Lipoic Acid
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patients, marked glutamine depletion develops in time, and Alpha-lipoic acid (α-LA) is essential to cell energy
the development of cachexia is accompanied by massive metabolism. It achieves antioxidant effects by reducing
depletion of glutamine in skeletal muscle. Glutamine has oxidative stress and increasing the glutathione (GSH)
25
demonstrated safe and neuroprotective effects in rat models peroxidase activity. 42-44 α-LA is also thought to be able to
of vincristine-, paclitaxel- and cisplatin-induced peripheral counteract proinflammatory factors (such as IL-6 and TNF-α)
neuropathy without impairing the cytotoxic efficacy of or downregulate the expression of genes involved in
antineoplastic agents. 26,27 Two studies have revealed that inflammatory-related pathways. 45,46
glutamine is effective in high-dose paclitaxel-induced In human studies, α-LA has been shown to improve
peripheral neuropathy for reducing numbness, dysesthesia, insulin sensitivity, vasodilation, and polyneuropathy in
and motor weakness, as well as reducing loss of vibratory patients with diabetes mellitus. It has also shown protective
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sensation. 28,29 Another study found that glutamine effects against cisplatin- and paclitaxel-induced neurotoxicity
significantly reduced the incidence and severity of oxaliplatin- in vitro by preventing mitochondrial energetic failure,
induced neuropathy as well as the need for dose reduction of neuronal apoptosis, and axonal damage. One RCT evaluated
42
oxaliplatin in patients with colorectal cancer, without whether α-LA could prevent neuropathy from platinum-
affecting response to chemotherapy and survival. A recent based chemotherapy; however, the overall patient-reported
30
clinical trial also demonstrated that in children or adolescents neuropathy scores of the α-LA group and the placebo group
with vincristine-induced peripheral neuropathy, glutamine were not significantly different. Another randomized,
31
44
supplementation is well tolerated and associated with multicentric study reported that the intravenous injection
improvements in sensory function and self-reported overall form of α-LA can mitigate the symptoms of CIPN. Results
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QoL. However, a newer meta-analysis suggested that on the efficacy of α-LA seem to be inconclusive.
glutamine should not be routinely administered due to its
cost and a lack of significant decreases in CIPN grading, Glutathione
numbness, and muscle weakness. 32 GSH is a nucleophilic sulphur-containing tripeptide
thiol within almost all cells. It has several vital roles within a
Acetyl-L-Carnitine cell, including antioxidation, maintenance of the redox state,
ALC is a molecule derived from acetylation of carnitine modulation of the immune response, and detoxification of
in the mitochondria. Carnitine acetylation enables the xenobiotics. It has shown neuroprotective effects in patients
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function of acetyl coenzyme A and facilitates the elimination with cancer receiving platinum-based chemotherapy by
of oxidative products, thus providing an antioxidant function. preventing platinum from accumulating in the DRG without
ALC supplementation has shown neuroprotective, affecting the clinical activity of chemotherapeutic drugs. 49,50
neurotrophic, and analgesic effects in the peripheral nervous However, with respect to cancer, GSH metabolism is able to
system. In an animal study, treatment of rats with carnitine play both protective and pathogenic roles. In many normal
33
and carnitine esters significantly lowered circulating levels of and malignant cells, increased GSH levels are associated with
tumor necrosis factor-α (TNF-α) and interleukins (ILs), a proliferative response and are essential for cell cycle
which induce systemic inflammatory response. In another progression. Elevated GSH levels are observed in various
34
animal study, ALC treatment significantly reduced the level types of tumors, and such levels make the neoplastic tissues
of protein carbonyl groups in the brains of dogs both at more resistant to chemotherapy. Therefore, GSH analogues
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2- and 24-hour reperfusion after 10-minute cardiac arrest. have also been developed in attempt to improve cancer
35
Protein carbonyl groups are thought to be a marker of chemotherapy, some examples being GSH-S-transferase
oxidative tissue injury and increase significantly during inhibitors and prodrugs, glyoxalase 1 inhibitors, and
ischemia. S-nitrosoglutathione. Some RCTs have shown that GSH
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ALC reduced neuropathic pain and histopathological significantly reduces platinum-induced neurotoxicity. 49,50,53,54
changes from mitochondrial damage in a rat model of However, another clinical trial among 185 patients treated
paclitaxel-, oxaliplatin- and cisplatin-induced neuropathy. with paclitaxel/carboplatin failed to demonstrate any benefit
36
Currently, the studies of ALC on CIPN in humans remain of GSH.
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inconclusive. Some studies have shown improvement of
CIPN in patients treated with ALC in paclitaxel- or cisplatin- Omega-3 Fatty Acids
induced peripheral neuropathy, 37,38 whereas a recent double- Omega-3 fatty acids are polyunsaturated fatty acids with
blind RCT in women undergoing adjuvant taxane-based a double bond (C = C) at the third carbon atom from the end
chemotherapy found increased neuropathy. 39,40 In a study of of the carbon chain. Eicosapentaenoic acid (EPA) and
multiple myeloma patients who were administered docosahexaenoic acid (DHA), the main long-chain omega-3
intravenous bortezomib, ALC did not alter the incidence of fatty acids studied, have demonstrated efficacy in modulating
neuropathy. Despite the inconclusive evidence on the pain and reducing inflammation. EPA and DHA are
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41
effects of ALC in the treatment or prevention of CIPN, ALC polyunsaturated fatty acids (PUFAs) incorporated into the
is still believed to be an agent with high potential. phospholipid membranes of cells, including central and

46 ALTERNATIVE THERAPIES, JUL/AUG 2020 VOL. 26 NO. 4 Liu—Complementary Nutritional Supplements and Chemotherapy-induced