Amrita University
Amritapuri, Vallikavu, Kerala 690525
India
Tanu Sharma, Narendra Parihar, Someshwar Nath, Azad Singh, Savneet Kaur, Simendra Singh and Chandi Mandal.
In the recent years, there has been a surge in various forms of cancers especially in urban areas of India. Tumor recurrence and metastasis are the main causes of increased morbidity and mortality. In poor and developing countries like India chemotherapy is the choosen method of therapeutic intervention for different types of malignancies such as breast, prostate, pancreas, etc. Although general chemotherapy treatment is effective in controlling tumour growth but high doses of the treatment regimen often results in severe off-target toxicity to different organs including liver, kidney, heart, brain etc. (1) A large percentage of patients are unable to tolerate this toxicity and sometime it can also lead to life threatening complications. (2) Therefore, the primary objective of this study is to prevent this druginduced off-target toxicity. Omega 3 fatty acids (n-3FAs) such as DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) that are active components of fish oil play active role in preventing cancer growth and its metastasis. (3–5) We have recently identified that omega 3-fatty acids prevent breast cancer bone metastasis by targeting cancer stem cell marker CD44 and osteoclastogenic factor CSF-1(4, 5). With this background, the present study addresses the role of n-3FAs in preventing chemotherapeutic drug-induced off-target toxicity.
Methods
The cat fishes were divided into four groups (each group contains 4 fishes) for each set of experiments. Three different chemotherapeutic drugs etoposide, doxorubicin, cisplatin at higher dosages (4, 2, 2 mg/kg body wt respectively) and fish oil (60mg/kg body wt, DHA: EPA; 2:3) were administered to cat fish (Mangur) by gavage. After 6 days, cat fishes were sacrificed and different organs were isolated. SGPT and alkaline phosphatase (ALP) activity assays were performed to examine liver function and superoxide dismutase activity (SOD) assay was conducted to evaluate reactive oxygen species (ROS) level.
Results
Severe skin damages were observed both in doxorubicin and cisplatintreated cat fishes as compared to the control fishes, indicating side effects of chemotherapeutic drugs treatment. High level of SGPT as well as ALP activity was observed in liver samples of etoposide and doxorubicin – treated fishes, suggesting chemotherapeutic drug-induced liver toxicity. Mechanistically, we found that doxorubicin treatment showed significant decrease of SOD activity in liver samples in comparison to the control fishes, suggesting that chemotherapeutic drugs lead to organ toxicity presumably by increasing ROS levels (6). However, treatment of the fishes with n-3FAs of the fish oil led to a dramatic reduction of chemotherapeutic drug-induced skin damages. Also, low levels of SGPT and ALP activities were observed in the fishes given etoposide in combination with n-3FAs as compared to the fishes given etoposide alone. Similarly, fish oil also gave protection against doxorubicin-induced liver dysfunction. Our data further showed that n-3FAs treatment significantly increased etoposide and doxorubicin-inhibited SOD activity.
Conclusions
The study for the first time reports that the use of n-3FAs leads to a dramatic reduction of chemotherapeutic drug-induced skin damages and mitigates chemotherapeutic drug-driven liver dysfunction presumably by reducing ROS level. This study suggests that n-3FAs may possibly be used in combination with chemotherapeutic drugs to treat different cancers to reduce chemotherapeutic drugs-associated systemic toxicity and to increase anticancer activity. Ongoing research study will further address the role of n-3FAs on other off-target toxic effects of chemotherapeutic drugs.