|Year : 2012 | Volume
| Issue : 3 | Page : 308-313
A low dose of doxorubicin improves antioxidant defence system and modulates anaerobic metabolism during the development of lymphoma
Nibha Verma, Manjula Vinayak
Department of Zoology, Biochemistry and Molecular Biology Laboratory, Banaras Hindu University, Varanasi, Uttar Pradesh, India
|Date of Submission||23-Nov-2010|
|Date of Decision||21-Feb-2012|
|Date of Acceptance||28-Feb-2012|
|Date of Web Publication||17-May-2012|
Department of Zoology, Biochemistry and Molecular Biology Laboratory, Banaras Hindu University, Varanasi, Uttar Pradesh
Source of Support: University Grants Commission, India, under the CAS program, Conflict of Interest: None
Objective: The objective of the present study is to find low dose of doxorubicin (DOX) with cancer preventive activity and to check the implication of this low dose of DOX on antioxidant defence system during lymphoma growth in mice, as the clinical utility of anthracycline anticancer drugs, especially DOX is limited by a progressive cardiotoxicity linked to mitochondrial damage.
Materials and Methods: We selected a dose of DOX (0.90 mg/kg body weight of mouse), which is about 20 folds lower than clinically used dose for cancer treatment. The cancer preventive action is monitored by modulation of anaerobic metabolism. The effect of this dose on antioxidant defence system is analyzed by testing the activities of antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST). The activities of these enzymes were monitored at different intervals during the growth of lymphoma in mice.
Results: The activities of antioxidant enzymes, such as CAT, SOD, and GST, were found to decrease gradually during the growth of lymphoma in mice. The anaerobic metabolism was increasing with lymphoma growth. We report that about 20 folds lower dose of DOX enhances the activities of antioxidant enzymes and decreases anaerobic metabolism during the development of lymphoma. These enzymes of antioxidant defence system suppress oxidative stress and mitochondrial damage, whereas a decrease in anaerobic metabolism checks cancer growth.
Conclusions: The result suggests that dose cumulative cellular toxicity of DOX may be avoided by treating cancer in animals with lower doses of DOX in combination with other drugs.
Keywords: Antioxidant enzymes, cancer prevention, Dalton′s lymphoma, doxorubicin, reactive oxygen species
|How to cite this article:|
Verma N, Vinayak M. A low dose of doxorubicin improves antioxidant defence system and modulates anaerobic metabolism during the development of lymphoma. Indian J Pharmacol 2012;44:308-13
|How to cite this URL:|
Verma N, Vinayak M. A low dose of doxorubicin improves antioxidant defence system and modulates anaerobic metabolism during the development of lymphoma. Indian J Pharmacol [serial online] 2012 [cited 2020 Aug 4];44:308-13. Available from: http://www.ijp-online.com/text.asp?2012/44/3/308/96299
| » Introduction|| |
Doxorubicin (DOX) is a broad spectrum anthracycline antibiotic used to treat a variety of malignancies. It interferes with the production of genetic material and can kill rapidly dividing cells, such as tumor cells. It is considered as the drug of first choice in the treatment of breast cancer, childhood solid tumor, soft tissue sarcoma, multiple myeloma, and aggressive lymphomas.  It is more abundantly found as a natural product because it is produced by a number of different wild-type strains of Streptomyces. However, its utility is limited by dose cumulative cardiotoxicity and hepatotoxicity  mainly due to mitochondrial damage and cardiomyocyte apoptosis.  Redox activation of DOX to form reactive oxygen species (ROS) has been implicated in DOX-induced toxicity,  which are known mediators of tissue injury and diseases leading to cell proliferation, apoptosis, and carcinogenesis.  DOX-induced apoptosis is suggested to be linked in part to the formation or in the inhibition in scavenging of H 2 O 2 .  An organism is generally protected from damage caused by free radicals by means of its antioxidant defence system. DOX modulates glutathione and glutathione-dependent antioxidant systems. 
The cellular antioxidant defence system operates mainly via antioxidant enzymes, such as SOD, catalase (CAT), glutathione S-transferase (GST), glutathione peroxidase (GPX) and glutathione reductase (GR) apart from nonenzymatic antioxidants. The antioxidant enzymes neutralize highly reactive free radicals, and thus prevent uncontrolled generation of ROS. Thus the antioxidant enzymes pose a major role in protecting the organism against ROS-induced injuries.  Therefore, decrease in DOX toxicity by enhancement in the activity of antioxidant enzymes is proposed to help in prevention of malignant growth by DOX chemotherapy. Furthermore, tumor cells maintain a high glycolytic rate even under aerobic conditions leading to high rate of lactate formation and in turn lactate dehydrogenase (LDH) activity increases several folds.  Therefore, downregulation of LDH activity is supposed to control tumor growth.
A higher dose of DOX to rats is reported to cause inactivation of antioxidant enzymes, such as CAT, SOD, and GST, in heart and leads to toxicity in liver and other tissues. Therefore, the present study is undertaken to test the effect of lower doses of DOX on antioxidant defence system as well as on anaerobic metabolism in mouse during the development of lymphoma. Liver is the major metabolic organ and is responsible for defence against oxidative stress. Therefore, liver is selected for monitoring activities of antioxidant enzymes.
| » Materials and Methods|| |
All the chemicals of molecular biology and analytic grade have been used in the experiments. The chemicals are purchased from Sigma Aldrich chemicals, U.S.A.; E-Merck, India; Himedia, India; Sisco Research laboratory, India and BDH, India.
AKR strain mice are maintained as per the norms of Institutional Animal Ethical Committee at 25°C ± 2°C under 12 h light/dark cycle with ad libitum supply of standard mice feed and drinking water. AKR mice are used for our study because of their short life span (about 18 months) and high susceptibility for tumor development. Adult male mice (15-20 weeks old) are selected for the study.
Induction of Lymphoma in Mice
Lymphoma was introduced into male mice by serial implantation of live Dalton's lymphoma (DL) ascites cells. Each mouse received about 1 × 10 6 cells in 1 mL of phosphate buffer saline (PBS) (pH 7.4) through i.p. injection as mentioned earlier.  DL ascites cells were gifted by Prof. A. Sodhi, Banaras Hindu University, India.
Treatment of Doxorubicin to DL Mice
The animals were treated with DOX after getting approval for this study by IAEC. One batch of DL mice received DOX on the next day of DL implantation. DOX, procured commercially, was dissolved in autoclaved distilled water and was administered to adult mice by i.p. injection. The dose of DOX was 0.90 mg/ kg body weight (30 μg of DOX to each mouse). This dose was selected on the basis of previous report. 
Animals were grouped into 5 batches as follows:
Batch (i) Normal adult male (N) mice([n=5), (ii) Dalton's lymphoma transplanted (DL) mice ((n=35), (iii) DL mice treated with DOX (n=35), (iv) normal adult male mice treated with DOX (n=5). A group of 5 mice were sacrificed from both the batches 2 and 3 on days 1, 3, 6, 9, 12, 15, and 18 after DL implantation. Batch 4 included a group of 5 normal adult mice treated with DOX. Batch 5 contained untreated DL mice (5 in number). The mice of batch 4 and 5 were sacrificed on day 18.
Dalton's lymphoma is a non-Hodgkin's T-cell lymphoma. Non-Hodgkin's lymphoma can spread beyond the lymphatic system to almost any part of the body, including liver, bone marrow, and spleen. Secondary lymphoma growth in liver of DL mice has been confirmed earlier in our laboratory by histopathologic analysis.  Liver, being the major metabolic organ was selected for assay of antioxidant enzymes, whereas LDH activity was assayed in serum. All the experiments were repeated 3 times.
Assay of Antioxidant Enzymes
Tissue extract was prepared by homogenization of liver in hypotonic buffer containing 10 mM HEPES (pH 7.9), 7 mM, 2-mercaptoethanol, 1.5 mM MgCl 2 , 10 mM KCl, 1 mM phenyl methyl sufonyl floride (PMSF) and centrifugation at 16,000 g for 20 min. The supernatant obtained was used for enzyme assay. The enzymes were assayed by spectrophotometric analysis as well as by in-gel activity staining as reported earlier. 
Activity gel assay of CAT was analyzed by native Polyacrylamide gel electrophoresis (PAGE) on 7.5% polyacrylamide and the gel was stained by ferric cyanide method  with minor modifications. The principle of active staining involves the reaction of hydrogen peroxide with potassium ferric cyanide, thereby reducing it to ferrocyanide. The peroxide is oxidized to molecular oxygen. Ferric chloride reacts with ferrocyanide to form a stable, insoluble Prussian blue pigment. CAT signals its location by scavenging H 2 O 2 , causing transparent bands on the blue gel. The intensity of bands was analyzed using Alpha image analyzer system. The activity of CAT was measured by spectrophotometric method  with minor modifications determining the decomposition of H 2 O 2 at 240 nm. One milliliter of the assay mixture contained phosphate buffer (pH 7.0), H 2 O 2 , and the enzyme source. One unit is the amount of enzyme that decomposes one micromole H 2 O 2 per min at 37°C.
Isozymes of SOD were separated by 10% PAGE and were analyzed by the photochemical method of Fridovich  with minor modifications. Activity of SOD was measured according to the method of Winterbourn et al.  with minor modifications by measuring the reduction of nitro blue terazolium chloride (NBT) at 560 nm. One unit is defined as the amount of enzyme causing half the maximum inhibition of NBT reduction.
The enzyme GST was assayed by measuring the formation of conjugate of glutathione and 1-chloro-2-,4-dinitrobenzene (CDNB) according to the method of Habig et al.  The reaction was performed in a final volume of 1 mL containing cellular protein, 1 mM CDNB, and 1 mM GSH in 100 mM phosphate buffer, pH 7.0. The activity was calculated by using extinction coefficient of 9.6 mM -1 cm -1 for CDNB. Activity is expressed as the amount of enzyme forming one nanomole of CDNB-GSH complex per minute.
Assay of Lactate Dehydrogenase
LDH assay was performed by spectrophotometric method as well as by native gel analysis by the method of Pathak and Vinayak.  LDH isozymes were separated by 7.5% polyacrylamide gel electrophoresis and activity staining was done with NBT/ phenyl metho sulphate (PMS) in dark. Enzyme activity was determined by measuring the conversion of NADH to NAD + in a pyruvate utilizing reaction at 1-min interval for 10 min at 340 nm. Protein was estimated according to the method of Bradford. 
One-way analysis of variance followed by Bonferroni t test was performed to evaluate the significant difference between the different batches and comparison has been made with DL mice. The significant difference between the different groups within the batch is compared with normal mice. values were expressed as mean ± standard error of mean from 3 independent experiments. P value <0.05 was considered statistically significant.
| » Results|| |
Changes in enzyme activities during growth of lymphoma
Activities of the antioxidant enzymes CAT, SOD, and GST as well as that of LDH were monitored during the development of lymphoma from next day of lymphoma transplantation till day 18 (D18). Enzyme activities were found to vary gradually with the development of lymphoma.
Activities of the Enzymes of Antioxidant Defence System
The activities of CAT, SOD, and GST were decreasing progressively as lymphoma advanced. CAT activity was only about 33% on D18 compared with normal mouse liver [Figure 1]a and b. However, activity of SOD was decreased to a lesser extent as compared with that of CAT. SOD activity was lowered to about 83% of the activity in normal mouse liver on D18 [Figure 2]a and b. The decrease in activities of antioxidant enzymes CAT and SOD activity may be due to increasing oxidative stress with the development of lymphoma. Increased oxidative stress in lymphoma-bearing mice in terms of lipid peroxidation and protein carbonylation has been confirmed in our laboratory, which is decreased by treating cancerous mice with various antioxidants. ,, Similarly, the activity of GST was found to decrease gradually with progression of lymphoma and it reached up to 55% activity on D18 as compared with that in normal mouse liver [Figure 3].
|Figure 1: a: 7.5% native PAGE and activity staining Catalase|
Figure 1: b: Densitometric scanning of Catalase
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|Figure 2: a: 10% native PAGE of Superoxide dismutase|
Figure 2: b: Densitometric scanning of Superoxide dismutase
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|Figure 3: Changes in activity and specific activity of Glutathione S transferase in mouse liver during development of lymphoma|
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Activity of LDH
The activity of LDH was checked in serum of normal as well as DL mice. The variation in LDH activity was monitored with progression of lymphoma from day 1 to day 18 after lymphoma transplantation. The activity was increased gradually from D1 to D18. It was elevated up to about 5 folds high on D18 [Figure 4]a and b. The level of isozyme A4 was found to increase with the progress of lymphoma. The increase in LDH activity is an indicator of increased anaerobic metabolism in DL mice, which is considered as a tumor marker. 
|Figure 4: a: 7.5% Native PAGE and activity staining of LDH isozymes|
Figure 4: b: Densitometric scanning of A4 Isozyme of LDH
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Effect of Doxorubicin on Antioxidant Enzymes During Development of Lymphoma
Antioxidant enzyme CAT remained almost constant up to day 12. A significant rise in the activity was found on day 15 onward [Figure 5]a and b. The maximum activity reached up to about 39% higher on D18 as compared with untreated DL mice. The activity was decreasing gradually with development of lymphoma in untreated mice. The result shows that DOX contributes to antioxidant defence system of the organism by maintaining CAT activity during development of lymphoma. Similar results were obtained in case of other enzymes of antioxidant defence system. The activities of both the isozymes of SOD were increased significantly in DOX-treated DL mice from day 3 to day 18 of lymphoma development [Figure 6]a and b. The highest enhancement in SOD activity was found on D18 where the activity was elevated up to about 45% high as compared with DL mice without drug treatment. The result demonstrates that DOX promotes the activity of antioxidant enzyme SOD. A similar rise in GST activity was observed after DOX treatment [Figure 7]. The activity was enhanced gradually till day 18 reaching up to about 70% on day 18 of DL implantation as compared with untreated DL mice.
|Figure 5: a: 7.5% native PAGE and activity staining of catalase|
Figure 5: b: Densitometric scanning of catalase
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|Figure 6: a: 10% native PAGE and activity staining of Superoxide dismutase|
Figure 6: b: Densitometric scanning of Superoxide dismutase
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|Figure 7: Changes in activity and specific activity of Glutathione S transferase in liver of DOX treated mice during development of lymphoma|
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Effect of doxorubicin on LDH during development of lymphoma
LDH activity was progressively increased with the development of lymphoma. However, after the treatment of DL-implanted mice with DOX, the LDH activity remained almost constant from day 6 to day 18 of DL mice [Figure 8]a and b.
|Figure 8: a: 7.5% native PAGE and activity staining of LDH isozymes|
Figure 8: b: Densitometric scanning of A4 isozyme of LDH
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The specific activities of antioxidant enzymes in mice liver were decreased during the development of lymphoma, which were gradually increased after DOX treatment. The results suggest that a low dose of DOX contributes to check cancer progression by improvement in antioxidant defence system along with downregulation of anaerobic metabolism.
| » Discussion|| |
Cancerous cells switch over to anaerobic metabolism using glycolysis as the source of energy (Warburg's effect) and hence LDH activity, especially the activity of anaerobic isoform LDH-A increases several folds in liver and other tissues as well as in serum. Therefore, increased serum LDH is considered as tumor marker. Increased LDH in various tissues as well as in serum of DL mice has been reported earlier. ,, In the present study the time-dependent progressive decrease in the activity of LDH during development of lymphoma by low dose (0.9 mg/kg) treatment of DOX indicates that DOX contributes to anticarcinogenic action by downregulation of anaerobic metabolism in tumor. This novel action of DOX is hereby reported in addition to its interaction with DNA by intercalation and stopping replication by inhibition of topoisomerase II.  Normally, human or experimental animals are given doses of DOX that ranges between 15 mg to 25 mg/ kg.  Cumulative dose of DOX of 550 mg/m 2 leads to a rise of developing cardiac side effects in human, including congestive heart failure, dilated cardiomyopathy, and death. , These effects are mainly due to ROS production. A cumulative dose of DOX of 550 mg/m 2 amounts to about 13.3 mg/kg. However, the use of DOX as a cancer therapeutic drug is still in practice because of its effective anticarcinogenic action. DOX is also useful in the treatment of HIV-1 as it is proposed to be used as conjugate with antienvelop antibody of HIV-1. 
Therefore, checking oxidative damage by combination therapy of DOX or by selecting a lower effective dose of DOX becomes essential. Heart SOD and CAT activities are found to be maintained with a lower dose of 5 mg/kg body weight.  Similarly a dose of 1 mg/kg/week for 7 weeks has been tested in rats.  A similar dose of 0.9 mg/kg is tested in the present study to check whether the oxidative damage caused by DOX can be reduced, without adversely affecting its anticancerous effects. LDH activity is used as a biomarker of cancer.  Decrease in LDH activity supports the anticancerous action of the present dose of DOX. The interesting finding is that this dose of DOX does not show adverse effects on the activities of antioxidant enzymes, such as CAT, SOD, and GST. Low dose of DOX during development of lymphoma leads to improvement in the decreased activities of antioxidant enzymes. The authors have earlier reported lower doses of DOX (0.45 mg, 0.9 mg, 1.35 mg/kg) to lymphoma-bearing mice is not toxic.  This increase in the activities of antioxidant enzymes may be a result of feedback regulation.  The antioxidant defence system is triggered by DOX treatment to activate the antioxidant enzymes. This may be due to more generation of ROS as redox activation of DOX to form ROS has been established earlier.  An increase in ROS level is compensated with organism's antioxidant defence system mainly by activating its antioxidant enzymes. However, generation of ROS beyond that limit by higher dose of DOX leads to inactivation of enzymes. Such damage of nucleic acid, lipid, and protein is well documented in the literature.  Although the efficiency of anticarcinogenic action of DOX might be reduced with the lower dose of DOX, it provides chance of giving multiple doses of DOX at regular intervals till cumulative dose reaches the risk level. Lower dose of DOX may be used as a therapeutic drug without costing for antioxidant defence system. The use of DOX at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and B16 melanoma resistant to DOX is recently suggested by Berezhnaya et al. 
There are several reports stating that the limited efficacy of DOX due to drug cumulative cardiotoxicity and drug resistance may be overcome to a certain extent by combination therapy of DOX. Several drugs and antioxidants have shown promising results to reduce DOX-induced nephropathy and cardiomyopathy. , However, these combination drug therapies do not overcome DOX toxicity completely.
In conclusion, the study suggests that low dose administration of DOX (0.9 mg/kg) could mitigate the activities of antioxidant enzymes in DL-treated mice and this dose could be advocated in combination with other anticarcinogenic drugs for chemotherapy of carcinogenicity.
| » Acknowledgment|| |
The authors thank Prof. Sodhi for the kind gift of DL ascites cells. Nibha Verma thanks Indian Council of Medical Research for providing Senior Research Fellowship. The work is supported by University Grants Commission, India, under the CAS program.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
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