2-Pyrocatechuic Acid Attenuates Carboplatin Induced Hematological Toxicities in Wistar Rats
Rohini R. Pujari1*, Deepti D. Bandawane2
1School of Pharmacy, Dr. Vishwanath Karad MIT World Peace University
Kothrud, Pune - 411038, Maharashtra, India.
2Department of Pharmacology, Modern College of Pharmacy,
Yamunanagar, Nigdi, Pune - 412105, Maharashtra, India.
*Corresponding Author E-mail: rohinirpujari@gmail.com
ABSTRACT:
Hematological toxicity or pancytopenia produced by carboplatin chemotherapy tends to limit the clinical usage of carboplatin as a potent antineoplastic agent. The current investigation was aimed at evaluation of the protective activity of a plant phenolic acid i.e. 2-pyrocatechuic acid (2,3 dihyroxybenzoic acid) against hematological adverse effects induced by carboplatin in Wistar rats. Intraperitoneal injection carboplatin (35 mg/kg) for 6 days resulted in significant alterations in hematological parameters such as decreased red blood cell, hemoglobin, total leukocyte and differential leukocyte counts and increased eosinophil counts in rat blood indicating severe hematological toxicities. Pre and co-administration of 2-pyrocatechuic acid at the doses 10, 30 and 100 with CP significantly attenuated the altered hematological indices in a dose-dependent manner exhibiting its efficacy as a protective agent for the amelioration and prevention of hematological toxicities induced by carboplatin chemotherapy.
KEYWORDS: 2-Pyrocatechuic acid; 2,3-Dihyroxybenzoic acid; Hematological toxicities; Carboplatin; Cancer chemotherapy.
INTRODUCTION:
Hematological toxicity is reported to be one of the major life-threatening adverse drug reactions produced by cancer chemotherapeutic agents which limits the efficacy and therapeutic value of these drugs as potent antineoplastic agents.1 The myelosuppression produced by these drugs leads to decreased production of blood corpuscles by the bone marrow by resulting in anemia caused by reduced erythrocyte production, leukocytopenia due to reduced leukocyte production and thrombocytopenia by decreased platelet production. This, in turn, increases the risk of life-threatening conditions such as detrimental opportunistic infections, different types of anemia and uncontrolled bleeding.2–4
Platinum complexes are amongst the most efficacious drugs utilized in the treatment of a broad spectrum of neoplasms. However, they are documented to produce detrimental adverse reactions including neural, renal and gastrointestinal toxicities as well as myelosuppression.5,6 Carboplatin (cis-diammine [1,1-cyclobutanedicarboxylato]-platinum [II]) is a new platinum-containing complex that is widely used clinically in the treatment of various types of malignancies such as head and neck cancer, small-cell lung cancer, ovarian, colorectal cancers, adrenocarcinomas and many more.7 Clinical use of the carboplatin has been hindered by various lethal adverse effects out of which myelosuppression being the major one. Carboplatin-induced myelotoxicity occurs in 20% to 30% of cases in a cumulative way and high-dose carboplatin (>1200 mg/m2) causes myelosuppression in >95% of cases. Its severity and occurrence increase noticeably in patients undergoing dialysis (25-100% cases).8,9 Myelosuppression including thrombocytopenia, leucopenia neutropenia and anemia causes delay, dose alterations, or discontinuation of carboplatin therapy.10 One of the important mechanisms of carboplatin-induced myelosuppression includes cross-linking with nucleic acids and proteins. Carboplatin consists of two chloride groups; these are substituted by molecules of water in an aquation reaction intracellularly. This aquated carboplatin complex reacts with various macromolecules such as proteins, DNA and RNA. Other mechanisms include increased release of reactive oxygen species and malondialdehyde, decreased glutathione (GSH) levels in the cells and disruption of mitochondrial function.11,12 Carboplatin also targets the hematopoietic stem cell fraction both in vitro and in vivo by depletion of colony-forming units (CFUs).13-15 The hematological adverse effects are manifested as severe anemia, leukocytopenia and thrombocytopenia.
A small number of modalities are utilized to counteract cancer chemotherapy-induced hematological toxicities such as blood transfusion, bone marrow transplantation and growth factors but these therapies tend to be very expensive, painful and complicated with inadequate efficacy in ameliorating the serious hematological complications. Searching different approaches to overcome the myelotoxicity devoid of added adverse with availability at a reasonable cost may be effective in improving the quality of life. Hence alternative therapy with lesser adverse effects and enhanced efficacy is the need of hour.16,17
Herbal drugs have played an important role in disease management and maintenance of health for many centuries. Bioactive molecules obtained from herbal drugs have become the center of research nowadays with a surge in demand for herbal medicines. They are not only used as a remedy for different ailments but also as good initiatives for drug discovery and development.18
Plant phenolic acids are such bioactive compounds obtained as secondary products abundantly found in edible nuts, vegetables and fruits.19,20 They are also documented for their chemoprotective activities against cancer chemotherapy-induced toxicities.21,22
2-Pyrocatechuic acid (2-PCA) has been documented to possess several pharmacological actions such as analgesic and anti-inflammatory activities, in vitro and in vivo antioxidant activities, antimutagenic and anticancer activities, antispasmodic and antirheumatic activities, iron chelating and siderophore activities, antiseptic, antifungal and antibiotic activities, protective activities against gentamycin and kanamycin induced ototoxicity and vancomycin induced nephrotoxicity.23-26 But 2-PCA has not yet been explored for its protective activity against hematological toxicities produced by any of the anticancer agents. In light of this, the present investigation was aimed to evaluate the adverse effects induced by CP on different hematological parameters in Wistar rats and the effect of 2-PCA (a plant phenolic acid) on these altered parameters.
MATERIAL AND METHODS:
Chemicals and kits:
2-Pyrocatechuic acid was purchased from Sigma- Aldrich Chemicals Co., St. Louis, MO, USA. Carboplatin (Paraplatin) was purchased from Glaxo Smith Kline Pharmaceuticals Ltd. Other chemicals and solvents used were of analytical grade and purchased from commercial suppliers. Heamcytometer, Sahli Hellige’s hemoglobinometer for estimations of hematological parameters were purchased from Kiran Enterprises, Pune, India.
Experimental Animals:
Adult Wistar rats of either sex (200-250 g) were used for the studies. They were procured from the National Institute of Biosciences (NIB), Pune, Maharashtra and caged in groups of 5-6 in standard polypropylene cages with a wire mesh top and maintained at standard environmental conditions at a temperature 25 ± 20C and 45 to 55% of relative humidity under 12 h light: 12 h dark cycle in the animal house of the institution. The animals had free access to food (Nutrivet Life Sciences, Pune, India). All the experiments were carried out between 12:00-16:00hours. The animals were transferred from the animal house to the experimental laboratory one hour before the start of the experiment.
Ethical clearance:
All the studies were carried out in accordance with the guidelines given by the Institutional Animal Ethical Committee (IAEC) as per the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), New Delhi, India (Section 15 of the Prevention of Cruelty to Animals Act, 1960; Ministry of environment and forest (AWD), Government of India). The protocol was approved by IAEC of Modern College of Pharmacy, Yamunanagar Nigdi, Pune- 411044. (Proposal No.: MCP/IAEC/004/2017; dated 07/11/2017).
Experimental design:
The rats were divided into five groups with 06 rats in each group. Group I and II served as normal control and 5-FU control groups respectively and received distilled water (1ml/kg) orally for 14 days. Groups III, IV, V and VI served as test groups and received 2-PCA at doses of 3, 10, 30 and 100mg/kg orally for 14 days. On the 9th day, all the groups except group I were administered with CP (35mg/kg) intraperitoneally which was continued further for the next five days up to the 14th day.27,28
Blood Sample collection:
At the end of the experimental period, blood was withdrawn from the retro-orbital plexus and transferred into heparinized tubes.29
Estimation of hematological parameters:
Estimation of red blood cell (RBC) counts:
The RBC counts were determined following the method of Raghuramulu et al., 1983 by hemocytometer using Neubauer's slide.29,30
Estimation of total leukocyte counts (TLC):
The TLC counts were determined following the method of Raghuramulu et al., 1983 by hemocytometer using Neubauer's slide.29,30
Estimation of differential leukocyte counts (DLC):
The DLC counts were determined following the method of Dacie & Lewis, 1984 by hemocytometer using Neubauer's slide.29,31
Estimation of hemoglobin content:
The hemoglobin contents were determined following the method of Varley, 2005 using Sahli Hellige's hemoglobinometer.29,32
Estimation of platelet count:
The platelet counts were determined following the method of Samuel, 1986 by hemocytometer using Neubauer's slide.29,33
Statistical analysis:
The results were expressed as mean + SEM. Comparison between the groups was made by one-way analysis of variance (ANOVA) followed by Tukey's Kramer Multiple Comparison test using Instat Graph Pad software (version-3).
RESULTS:
Estimation of RBC counts:
Administration of CP caused a significant (P<0.001) reduction in the RBC counts in the CP control group as compared to the normal control group. Pre- and co-administration of 2-PCA at the doses of 10, 30 and 100 mg/kg exhibited a significant (P<0.05, P<0.01 and P<0.001 respectively) elevation in the RBC counts relative to the CP control group in a dose-dependent manner (Table 1).
Estimation of total leukocyte counts (TLC):
The CP control group showed a significant (P<0.001) reduction in TLC counts as compared to the normal control group. Pre- and co-treatment of 2-PCA at the doses 10, 30 and 100mg/kg with CP showed a significant (P<0.05, P<0.01 and P<0.001 respectively) and dose dependant enhancement in the TLC counts as compared with CP control group (Table 1).
Estimation of differential leukocyte counts (DLC):
Administration of CP caused significant (P<0.001) elevation in the eosinophil count, while significant lowering in neutrophil (P<0.001), basophil (P<0.01), monocyte (P<0.01) and lymphocyte (P<0.001) counts in the carboplatin control group as compared to the normal control group. Pre and co-treatment of 2-PCA at the doses of 10, 30 and 100mg/kg with CP exhibited significant (P<0.05, P<0.01 and P<0.001 respectively) decline in the eosinophil count and significant (P<0.05, P<0.01 and P<0.001 respectively) increase in neutrophil, basophil, monocyte and lymphocyte count in a dose-dependant manner in comparison with CP control group (Table 1).
Estimation of hemoglobin (Hb) content:
CP caused a significant (P<0.001) lowering of Hb contents in the CP control group relative to the normal control group. CP group pre and co-treated with 2-PCA at the doses 10, 30 and 100mg/kg showed significant (P<0.05, P<0.01 and P<0.001 respectively) increase in Hb contents in a dose-dependent manner as compared to CP control group (Table 1).
Table - 1: Effect of CP and 2-PCA on hematological parameters
|
Experimental Groups |
Hematological parameters |
||||||||
|
RBCs (Million/mm3) |
Hb count (%) |
Platelets (Lakhs/mm3) |
TLC (/mm3) |
Eosinophils(%) |
Basophils (%) |
Neutro-phils (%) |
Lymphocytes (%) |
Monocytes (%) |
|
|
Normal Control |
6.63± 0.08 |
14.8± 0.17 |
3.57± 0.05 |
7100± 22.80 |
1.08± 0.02 |
2.97± 0.18 |
61.76± 5.34 |
32.90± 4.11 |
7.01± 2.05 |
|
CP Control |
3.23± 0.05*** |
7.51± 0.15*** |
1.45± 0.03*** |
2750± 9.87*** |
6.76± 0.25*** |
1.16± 0.02*** |
31.65± 6.35*** |
15.44± 6.21*** |
3.45± 1.56*** |
|
2-PCA (3) + CP |
3.85± 0.05 |
7.85± 0.10 |
1.89± 0.02 |
2978± 10.15 |
6.18± 0.56 |
1.24± 0.03 |
32.33± 4.45 |
25.97± 4.28 |
3.31± 2.09 |
|
2-PCA (10) + CP |
4.98± 0.07# |
9.90± 0.74# |
2.78± 0.04# |
4645± 11.76# |
4.02± 0.67# |
1.88± 0.04# |
55.53± 3.15# |
29.37± 3.75# |
5.81± 2.54# |
|
2-PCA (30) + CP |
5.87± 0.08## |
11.56± 0.54## |
3.19± 0.04## |
5945± 11.26## |
3.11± 0.76## |
2.11± 0.01## |
57.07± 6.88## |
30.87± 3.27## |
6.12± 2.10## |
|
2-PCA (100) + CP |
6.23± 0.07## |
13.97± 0.88### |
3.59± 0.08### |
6985± 10.12### |
1.43± 0.09### |
3.01± 0.03### |
62.03± 7.15### |
33.27± 2.48### |
7.35± 2.37### |
Results were expressed as mean + SEM (n=6). Comparison between the groups was made by one-way analysis of variance (ANOVA) followed by Tukey's Kramer Multiple Comparison test ***P<0.001 as compared to normal control. #P<0.05, ##P<0.01, ###P<0.001 as compared to CP induced control.
Estimation of platelet counts:
A significant (P<0.001) decrease in the platelet counts was observed in the CP control group relative to the normal control group. Pre and co-treatment of 2-PCA at the doses 10, 30 and 100mg/kg with CP significantly (P<0.05, P<0.01 and P<0.001 respectively) and dose-dependently enhanced the platelet counts as compared to the CP control group (Table 1).
DISCUSSION:
Hematological disorders caused by cancer chemotherapy have been reported to cover almost the complete field of hematology, influencing white blood cells, red blood cells, platelets and the blood clotting system thereby increasing the risk of anemia, potentially fatal opportunistic infections and uncontrolled hemorrhage respectively, which proves to be life-threatening to the patients.34,35
Carboplatin, a heavy metal-based complex is a non-classical alkylating agent which is used widely as a potent anticancer agent against various types of cancers including head and neck cancer, lung cancer, gynecological malignancies, and many more. Carboplatin is the first drug of second-generation platinum complexes introduced clinically in 1981. The clinical efficacy of carboplatin is hampered by lethal adverse effects which myelosuppression being the important one.36
Myelosuppression produced by carboplatin results in delay, dose modifications and discontinuations of chemotherapy. The mechanism of carboplatin-induced myelosuppression includes oxidative stress, targeting of the hematopoietic stem cells by DNA cross-linking, and enhanced lysis of blood corpuscles. Alterations in the hematological indices not only indicate the toxic effects of cancer chemotherapy but also reveal the physiological and pathological status of the body.37 Hence in the present investigation we estimated all the hematological parameters in order to confirm hematological toxicities induced by CP.
CP caused severe alterations in hematological parameters which included a severe decrease in the RBC count, Hb, platelet count, total leukocyte count (TLC), basophil, neutrophil, lymphocyte and monocyte counts and increase in eosinophil count as compared to normal control showing severe hematological toxicities. A decrease in the RBC count and Hb content indicated severe anemia produced by CP. These alterations may be due to excessive erythrocytosis or inhibition of erythropoesis.38,39
In the present study, these counts were reverted to the normal by pre and co-administration of 2-PCA with CP rendering it as an efficacious alternative armamentarium against CP induced anemia. 2-PCA has been documented for its iron-chelating activities which have been evidenced for their usefulness in the treatment of thalassemia patients. Apart from this, it has been also documented to be an endogenous siderophore and its deficiency can cause splenic overload and anemia in mice. These reports may also be mechanistically correlated in these regards.40,41
Reduction of total leukocyte count or leukocytopenia is reported to be associated with the fatalities due to severe opportunistic infections of patients receiving cancer chemotherapy.42,43 In the current study pre and co-treatment of 2-PCA with CP enhanced the reduced levels of neutrophils indicating its immunostimulant and protective activity against CP induced leukocytopenia and associated fatalities.44,45
Chemotherapy-induced neutropenia is documented to be the most severe and frequently occurring adverse effect of cancer chemotherapy which usually enhances the risk of life-threatening infections, especially in geriatric, pediatric and immunocompromised patients.46-48 In the current investigation, pre and co-treatment of 2-PCA with CP restored the decreased levels of neutrophils to normal indicating its immunostimulant and protective activity against CP induced neutropenia and its ability to reduce fatal outcomes in immunocompromised patients.
Basopenia (basocytopenia) is a type of granulocytosis characterized by a reduction in basophil count. It is one of the important hematological side effects produced by anticancer agents which tends to increase the susceptibility of patients towards opportunistic infections.49,50 Basopenia produced by CP was successfully overcome by 2-PCA indicating its immunostimulant and protective activity against CP induced basocytopenia which may be again contributed to their immunomodulatory properties.
Chemotherapy-induced leucocytosis is documented to cause severe lymphocytopenia that may alter the immune function in patients of chemotherapy by reducing endogenous and regulatory cells that are responsible for the activation of cytokines.44 Pre- and co-administration of 2-PCA with CP reverted the lymphocyte count to normal exhibiting its immunostimulant and protective activity against CP induced lymphocytopenia.
Monocytopenia produced as a result of cancer chemotherapy is a type of leukocytopenia which is characterized by a deficiency of monocytes. It occurs due to the apoptosis produced by DNA cross-linking in monocytes. Cancer chemotherapy-induced monocytopenia is reported to be a major risk factor for neutropenia and consequences associated with it.51 Pre and co-treatment of 2-PCA with CP successfully enhanced monocyte count to normal indicating its immunostimulant and potential protective activity against CP induced monocytopenia and in turn neutropenia and related consequences. 2-PCA and its own ethyl ester derivative (DHB-EE) were investigated for their actions on monocytes exposed to increasing H2O2 concentrations in a study by Graziano et al., 1976, wherein 2-PCA showed protective activity on monocytes against harmful actions of H2O2 by the virtue of both antioxidant and iron-chelating properties. These mechanisms can be correlated with the results of the present study.52
Enhanced eosinophil count (eosinophilia) is documented as a marker of allergic reactions produced by chemotherapeutic drugs.53 Pre- and co-treatment of 2-PCA with CP restored eosinophil counts to the normal indicating its antiallergic property against CP induced allergic reactions.
Immunostimulant and protective effects of 2-PCA against CP induced leukocytopenia, neutropenia, basopenia, lymphocytopenia and monocytopenia may be attributed to previously documented immunomodulatory properties of 2-PCA.23,45
Cancer chemotherapy-induced thrombocytopenia is a major adverse effect that leads to reduced blood coagulation resulting in continuous bleeding. This, in turn, may exaggerate the cancer chemotherapy-induced anemia as a secondary effect54. Pre and co-treatment of 2-PCA with CP prevented the decrease in thrombocyte counts and showed normalized counts indicating their potential protective action against CP induced thrombocytopenia and blood loss. The anti-anemic effect of 2-PCA can also be attributed to its ameliorative effect against CP induced thrombocytopenia.
CONCLUSION:
Considering the results of the present study, it may be concluded that 2-PCA may be used to ameliorate and protect against hematological consequences induced by CP like anemia, leukocytopenia and thrombocytopenia. These abrogative effects can be attributed to the amelioration of myelosuppression. Further investigations are required to reveal probable molecular mechanisms involved in protective effects of 2-PCA
ACKNOWLEDGEMENT:
Authors are grateful to Dr. P. D. Chaudhari, Principal, Modern College of Pharmacy, Nigdi, Pune and Dr. S. N. Dhole, Principal, Modern College of Pharmacy (For Ladies), Moshi, Pune for providing facilities, guidance and support.
CONFLICT OF INTEREST:
The authors declare no conflict of interest.
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Received on 23.12.2020 Modified on 10.03.2021
Accepted on 14.04.2021 © RJPT All right reserved
Research J. Pharm.and Tech 2022; 15(3):1053-1058.
DOI: 10.52711/0974-360X.2022.00176