Protective Role of Alpha-Lipoic Acid in Chemotherapy-Induced Mucositis

Colorectal cancer (CRC) is characterized by abnormal growth of colon or rectum cells. It accounts for approximately 10% of all cancer cases, with the majority of cases occurring in older individuals aged 50 years and above .It is considered the third most common cancer globally (6.1%) after lung cancer in both female and male (11.6%), (breast cancer is the second common cancer in females) (11.6%) and (prostate cancer is the second common in males) (7.1%) .It is estimated that CRC cases will rise by 71.5% among males and by 60% among females by 2035. It stands as the second most common cause of cancer-related mortality worldwide, accounting for 9.2% of all cases (9% male and 8% female).

Surgery remains the primary curative treatment for localized disease and is considered the most definitive treatment for colon cancer, while systemic chemotherapy is utilized across neoadjuvant, adjuvant, and metastatic settings. Commonly used chemotherapy protocols include 5-fluorouracil in combination with oxaliplatin or irinotecan. Hence, 5- fluorouracil (5-FU) is considered the backbone of CRC chemotherapy.

As an analogue of pyrimidine, the mechanism of 5-FU cytotoxicity is via competitive inhibition of thymidylate synthetase with consequent thymidine deficiency resulting in inhibition of deoxyribonucleic acid (DNA) synthesis. In addition, incorporation into ribonucleic acid (RNA) interferes with RNA processing and function.

However, despite its efficacy, the continuous infusion of 5-FU is frequently complicated with many toxicities including neutropenia, hand-foot syndrome (HFS), diarrhea, nausea, vomiting and mucositis due to non-selective cytotoxicity on rapidly dividing cells.

Oral mucositis is a debilitating inflammatory reaction of mucous membrane which is a significant problem in patients undergoing chemotherapeutic management, such as 5-FU. Patients experience symptoms ranging from oral pain and dysphagia to severe diarrhea and malnutrition, significantly compromising quality of life and treatment adherence. These effects can lead to chemotherapy dose modifications or interruption, eventually affecting therapeutic outcomes and contributing to infection-related death, emphasizing the need for effective management strategies. Several risk factors predispose patients to develop mucositis such as old age, female gender, overweight, dihydropyrimidine dehydrogenase deficiency, a critical enzyme for 5-FU catabolism, reduced drug clearance and genetic susceptibility.

While mucositis can affect the entire gastrointestinal tract, OM represents a significant clinical challenge owing to its impact on essential functions including speech, mastication, and swallowing, which disturbs nutritional intake and quality of life in cancer patients. The incidence of oral mucositis (OM) with 5-FU of grades 1 and 2 is nearly 93% in CRC cancers.

The pathophysiology of chemotherapy induced OM is comprised of a complex process of five stages, including initiation, signaling, amplification, ulceration, and healing.

During the initiation phase, tissue injury results in the death of the basal epithelial cells and the generation of reactive oxygen species due to dysfunction in the antioxidant protective pathway enzymes including glutathione (GSH), superoxide dismutase (SOD), catalase, myeloperoxidase (MPO), and hydrogen peroxide thereby leading to oxidative stress. This oxidative stress is associated with elevated levels of malondialdehyde (MDA) and 4-hydroxynonenal, although visible symptoms are absent at this stage.

The signaling phase occurs within hours to several days after the initial insult, where upregulation of pro-apoptotic signaling pathways such as nuclear factor kappa B (NFκB) promotes pro-inflammatory cytokine production such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). In that stage mild erythema becomes evident.

During the signal amplification phase, occurring on days 3-5 depending on the regimen, inflammatory pathways such as TNF-α are amplified causing further cellular damage and death. Additionally, matrix metalloproteinases (MMPs) (especially MMP-1 and MMP-3) are activated, leading to degradation of the extracellular matrix and epithelial connective tissue interface, resulting in increased erythema and soreness.

The ulceration phase typically occurs around day 5-10 after chemotherapy or during the second week of radiotherapy. This phase is characterized by epithelial breakdown resulting in visible painful ulcers covered with a fibrinous pseudo membrane (grayish-white appearance). Bacterial colonization in the ulcer bed activates macrophages, stimulating release of TNF-α, IL-1β, thus exacerbating inflammation.

Finally, the healing phase starts once chemotherapy or radiotherapy is discontinued or completed, during which epithelial proliferation is initiated, thus restoring tissue integrity.

Chemotherapy-induced ROS play a key role in the development of OM, a fact that has led to the evaluation of the oxidative stress pathway as a potential target for OM prevention and management.

Studies investigating oxidative stress and the role of antioxidants, in the context of chemo induced OM, have assessed their effects on mitigating the severity of OM in various settings.

As in previous clinical study reported that curcumin, due to its antioxidant and anti-inflammatory effects, promoted rapid recovery and reduced OM severity in chemotherapy-induced cases.

In another previous clinical study reported that oral zinc sulfate reduces the incidence and severity of chemo induced OM, pain, and dry mouth by its antioxidant effect.

In another previous clinical study reported that silymarin reduced severity and delayed onset of mucositis by its antioxidant effect.

Despite these efforts, no standardized prophylactic therapy has been established. Current management remains mostly supportive, focusing on good oral hygiene, and analgesia.

Alpha-lipoic acid (ALA) (1,2-dithiolane-3-pentanoic acid, ALA) and its reduced form, dihydrolipoic acid (DHLA), are naturally occurring antioxidants found in both plants and animals. Clinically, it is a supplement for managing chronic diseases characterized by oxidative stress, notably diabetic neuropathy, demonstrating promise in slowing the onset of metabolic syndrome through antioxidant properties. The dosage range of ALA that can produce favorable effect is(600mg/day-1800mg/day) without experiencing any harmful adverse effects. The most common adverse effects reported with ALA are headache, heartburn, nausea, and vomiting.

ALA can mitigate ROS production by regenerating endogenous antioxidants such as glutathione, vitamin E, and C, in addition to its metal chelation activity, thus causing significant decline in the serum levels of oxidative stress markers such as MDA. A previous clinical study reported that ALA at a dose 300 mg twice daily for 4 months significantly decreased MDA in type-1 diabetic patients with subclinical left ventricular dysfunction. Another study reported that higher doses of ALA, 600 mg twice daily for 3 months, significantly decreased MDA in patients with non-alcoholic fatty liver disease.

Moreover, ALA exhibited strong anti-inflammatory effects. In a preclinical study, ALA significantly decreased IL-1β in lipopolysaccharide-induced endothelial fractalkine expression. In another study evaluating the protective effect of ALA against bone destruction in mice, ALA significantly decreased IL-1β levels .Moreover, ALA inhibited proinflammatory pathways mediated by NF-κB, TNF-α, and IL-6, while enhancing the activity of the anti-inflammatory protein nuclear factor erythroid 2-related factor 2 (Nrf2), thereby reducing tissue damage .

Due to the previously mentioned benefits, ALA has been suggested as a potential candidate for mucositis prevention. A study that evaluated the protective effects of ALA against 5FU-Induced gastrointestinal mucositis in rats reported that ALA treatment decreased TNF-α/IL-1β, MDA, and (matrix metalloproteinases) MMPs/TIMP-1( tissue inhibitor of metalloproteinases 1), while it increased SOD (superoxide dismutase) and GPx (glutathione peroxidase) compared to untreated controls ,ALA also ameliorated severe mucosal damage (degeneration of epithelial cells, edema, villus irregularities) in stomach and small intestine.

In a rat model of methotrexate induced oral mucositis, ALA significantly decreased MDA levels while restoring the antioxidant defense system by increasing activities of SOD and catalase, along with elevated GSH compared to the control group. ALA also markedly reduced the expression of TNF-α and caspase-3 expression in oral epithelial cells and improved histological appearance of the mucosa with less tissue degeneration and fewer ulcerations. Therefore, ALA, might be a potential protective agent against 5-FU-induced mucositis in CRC patients, by mitigating oxidative stress and inflammation.