Body Weight Doxorubicin Research Articles

Mitigating Doxorubicin-Induced Cardiotoxicity through Quercetin Intervention: An Experimental Study in Rats.

Doxorubicin (DOX) is an effective anticancer drug, but its use is limited by dose-dependent heart toxicity. Quercetin is a natural antioxidant frequently studied for its beneficial properties. Moreover, a wide range of dietary supplements are available for human use. This in vivo study aimed to explore the potential cardioprotective effects of quercetin in chronic DOX treatment. A total of 32 Wistar rats were randomly divided into four groups: control, DOX, DOX/Q-50, and DOX/Q-100, treated with saline, 2.5 mg/kg body-weight DOX, 2.5 mg/kg body-weight DOX + 50 mg quercetin, and 2.5 mg/kg body-weight DOX + 100 mg quercetin, respectively, for two weeks. Rats were monitored using cardiac ultrasound (US) and markers for cardiac injury. Oxidative damage and ultrastructural changes in the heart were investigated. Chronic DOX treatment led to a decline in cardiac function and elevated values of NT pro-BNP, troponin I, and CK-MB. Quercetin treatment slightly improved certain US parameters, and normalized serum NT pro-BNP levels. Furthermore, DOX-induced SOD1 depletion with consequent Nrf2 activation and DNA damage as shown by an increase in γH2AX and 8HOdG. Quercetin treatment alleviated these alterations. Oral administration of quercetin alleviated serum markers associated with DOX-induced cardiotoxicity. Furthermore, it exhibited a favorable impact on the cardiac US parameters. This suggests that quercetin may have potential cardioprotective properties.

MO11 and MS06 ameliorated cadmium chloride-induced neuro-degeneration and alterations of dopamine, glutamate and myelin basic protein expressions in rats

This study evaluated the neuro-protective potentials of MO11 (isolated from Moringa oleifera leaves) and MS06 (isolated from Musa sapientum suckers) in Cadmium Chloride (CdCl2)-induced neurotoxicity in rat cerebrum. Twenty-eight adult male wistar rats were randomly divided into 7 groups (n= 4). Group 1 received physiological saline. Groups 2-4 and 7 received single 1.5 mg/Kg bodyweight of CdCl2 (i.p.) (Day 1). Groups 3, 4 and 7 were post-treated with 15 mg/Kg bodyweight of MO11, 15 mg/Kg bodyweight of MO11 + 7 mg/Kg bodyweight of MS06 and 3.35 mg/Kg bodyweight of Doxorubicin respectively (Days 1-17). Groups 5 and 6 received only MO11 and Olive Oil (vehicle) respectively (Days 1-17). Tissue-immunochemical assays of Dopamine, Glutamate and Myelin Basic Protein (MBP) (ELISA technique) and Total Protein assays (spectrophotometric technique) in cerebral homogenates of rats were conducted. Statistical analyses showed upregulations of Dopamine and Glutamate in Groups 3, 4 and 7 compared with Group 2. Furthermore, results showed significant MBP-downregulations in Groups 3 and 4, but non-significant MBP-downregulation in Group 7, compared with Group 2. Total Protein levels were normal in Groups 1-7. MO11 and MS06 provided better neuro-protective and re-myelination potentials compared with Doxorubicin. Overall, MO11 and MS06 possess neuro-protective, neuro-regenerative and re-myelination potentials.

Assessment of the ameliorative potential of A. cepa and its fractions on doxorubicin-induced cardiotoxicity in Wistar rats

The assessment of the ameliorative potentials of A. cepa and its fractions on doxorubicin-induced cardiotoxicity in Wistar rats was evaluated in this study. 45 Wistar rats of both sexes were randomly divided into 9 groups of 5 animals each; as follows: group I, served as control and received 10 ml/kg body weight of 0.9% saline, group II, 10mg/kg body weight of doxorubicin, group III, 4 mg/kg body weight of vitamin E plus Dox. Group IV, 1000mg/kg body weight of crude extracts of A. cepa plus Dox. Group V, 1000mg/kg body weight of n-hexane fraction of A. cepa plus Dox. Group VI, 1000mg/kg body weight of DCM fraction of A. cepa plus Dox. Group VII, 1000mg/kg body weight of EA fraction of A.cepa plus Dox. Group VIII, 1000mg/kg body weight of methanol fraction of A. cepa plus Dox, and group IX, combinations of 1000mg/kg, 4mg/kg 10mg/kg body weight of crude extract of A. cepa, vitamin E and Dox respectively for 16 days. Groups I and II treatments lasted 14 days, while treatments for groups III-VIII lasted 16 days (making 14 day for respective treatments and addition 2 days for doxorubin administered once 48 hourly) before sacrificing. All substances in this study were administered orally except doxorubicin that was done intravenously. The results showed that doxorubicn administration (group II) significantly (p<0.05) elevated troponin and NO levels; CK and LDH activities, compared to the control group indicating cardiotoxicity. This cardiotoxic effect of doxorubincin was significantly reversed by administration of vitamin E, crude extract, DCM, n-hexane to groups III, IV, V and VI respectively. A significant (p<0.05) reduction of only NO was recorded with EA fraction, compared with group II (dox). Methanol fraction (group VIII) further escalated doxorubicin-induced cardiotoxicity with a significantly (p<0.05) elevated myoglobulin and NO levels and CK activity. But the combined treatment with vitamin E, Crude extract and dox significantly (p<0.05) reduced cardiotoxic markers in this study except myoglobulin where a significant (p<0.05) elevation was recorded. It can be concluded that fresh A. cepa leaves extract possesses cardio-protective properties and may be a suitable cardio-protector against drug-induced cardiotoxicity in crude extract form, fractions of DCM and n-hexane but definitely not with methanol fraction as shown in this study.

Anticancer effect of Triphala extract on the hepatocellular carcinoma cells in mice

Context: Triphala is a traditional herbal formulation consisting of dried fruits from three plants namely, Terminalia bellirica, Terminalia chebula and Phyllanthus emblica. Its traditional used to treat many ailments, including various types of cancers, health promotion, and longevity. Aims: To evaluate the ability of an aqueous extract Triphala (TPL) to inhibit the growth of Hepatocellular carcinoma cells (HepG2) and in mice. Methods: The anticancer activity of TPL and its composite extracts was assessed in vitro by MTT assay with HepG2 cells. The mice were inoculated with HepG2 cells and then divided randomly into six groups (6 mice/group): control group, positive control group (intraperitoneal with 3 mg/kg body weight doxorubicin), and TPL treatment groups (oral administrated with 50, 100, and 200 mg/kg body weight TPL, respectively). Anticancer activity based on body weight, tumor growth volumes, survival time, relative organ weight, and hematological parameters was determined after administrating the TPL for 14 consecutive days. Results: The results demonstrated that the TPL extract exhibited antiproliferative activity against HepG2 cells in a time-dependent manner of treatment. The selectivity index (SI) showed that TPL is highly selective (SI>3) against the HepG2 cell line and has no activity against non-tumor cells. Oral administration with TPL extract at the dose of 200 mg/kg body weight inhibited tumor growth volume and increase the survival time. No abnormality of hematological parameters, relative organ weight, body weight, and morphology of organs were observed. Conclusions: The TPL extract at the test doses was a non-toxic drug. Our finding reveals the anticancer efficacy of TPL extract.

In vivo anti-inflammatory effects of anti-toxic principles from Moringa oleifera(MO11) and Musa sapientum (MS06) via NF-KB/IL-4/IL-10- mediated pathway in Cadmium Chloride-induced hepato-toxicity.

Cadmium-induction of hepato-toxicity and inflammation in animal models have been reported. The mechanism underlying hepatic inflammation is poorly understood. This study evaluated antiinflammatory potentials of MO11 (isolated from Moringa oleifera leaves) and MS06 (isolated from Musa sapientum suckers) in Cadmium Chloride (CdCl)-induced hepato-toxicity and inflammation in rats.Twenty-eight adult male wistar rats (average weight of 155 g) were randomly divided into 7 groups (n = 4). Group 1 was control. Groups 2 - 4 and 7 received single intraperitoneal administration of 1.5 mg/Kg bodyweight of CdCl on Day 1. Thereafter, Groups 3, 4 and 7 were post-treated with 15 mg/Kg bodyweight of MO11, 15 mg/Kg bodyweight of MO11 + 7 mg/Kg bodyweight of MS06 and single-dose of 3.35 mg/Kg bodyweight of Doxorubicin respectively (Days 1 - 17). Groups 5 and 6 received only MO11-dose and Olive Oil (vehicle) respectively (Days 1 - 17). Liver histopathology (Heamatoxyline and Eosin technique) and ELISA concentrations of proinflammatory biomarkers (IL-1β, IL-6, IL-8 and NF-kB) and anti-inflammatory biomarkers (IL-4 and IL-10) in liver homogenates of rats of Groups 1 - 7 were evaluated. Computed data were statistically analysed using Mann-Whitney-U test at P ≤ 0.05. Histo-pathological analyses showed normal liver histology in Groups 1 - 7. Post-treatments of CdCl-induced hepato-toxicity and hepatic inflammation with MO11 and MO11+MS06 resulted in downregulations of IL-1β, IL-6, IL- 8 and NF-kB, but upregulations of IL-4 and IL-10 in Groups 3, 4 and 7, compared with Group 2. MO11 and MS06 possess hepato-protective and anti-inflammatory potentials.

Cadmium Chloride-induced skin ulceration and inflammation in rats: Anti-inflammatory potentials of Moringa oleifera and Musa sapientium via NF-KB/IL-4/1L-10-mediated pathway.

Cadmium-induced toxicity resulted in skin carcinogenesis in rats. The mechanism underlying Cadmium-induced skin carcinogenesis remains poorly understood. Therefore, we evaluated anticancer potentials of Moringa oleifera and Musa sapientum in Cadmium Chloride (CdCl2)-induced skin carcinogenesis, ulceration and inflammation in rats. Twenty-eight adult male wistar rats (average weight of 155 g) were randomly divided into 7 groups (n = 4). Group 1 was control. Groups 2-4 and 7 received single intraperitoneal administration of 1.5 mg/Kg bodyweight of CdCl on Day 1. Thereafter, Groups 3, 4 and 7 were post-treated with 15 mg/Kg bodyweight of MO11, 15 mg/Kg bodyweight of MO11 + 7 mg/Kg bodyweight of MS06 and 3.35 mg/Kg bodyweight of Doxorubicin respectively (Days 1-17). Groups 5 and 6 received only MO11-dose and Olive Oil (vehicle) respectively (Days 1-17). Skin histopathology (Heamatoxyline and Eosin technique) and ELISA concentrations of pro-inflammatory biomarkers (IL-1β, IL-6, IL-8 and NF-kB) and antiinflammatory biomarkers (IL-4 and IL-10) in liver homogenates of rats of Groups 1-7 were evaluated. Computed data were statistically analysed using Mann-Whitney-U test at P ≤ 0.05. Histo-pathological evaluations showed normal skin histology in Groups 1 and 3-5, but skin histoalterations in Groups 2 and 6. Post-treatments of CdCl2-induced skin carcinogenesis with MO11, MO11+MS06 and Doxorubicin resulted in downregulations of IL-1β, IL-6, IL-8 and NF-kB, butupregulations of IL-4 and IL-10 in Groups 3, 4 and 6, compared with Group 2. MO11 and MO11+MS06 achieved better anti-inflammatory potentials than Doxorubicin. Overall, MO11 and MS06 possess anticancer and anti-inflammatory potentials.

Antitoxic Principles from Moringa oleifera (Mo11) and Musa sapientum (Ms06) Ameliorated Cadmium Chloride-Induced Renal Hyperplasia and Apoptosis through Ki67/P53-Mediated Pathway in Rats

Background: Cadmium (Cd) is an established carcinogen. Cd-induced renotoxicity resulted in oxidative stress, loss of excretory kidney functions, and apoptosis of murine kidney cells. Objectives: This study evaluated renoprotective potentials of MO11 (isolated from Moringa oleifera leaves) and MS06 (isolated from Musa sapientum suckers) against Cd chloride (CdCl2)-induced renotoxicity, renal hyperplasia, and apoptosis in rats. Materials and Methods: Twenty-four adult male Wistar rats (average weight of 155 g) were randomly divided into seven groups (n = 4). Group 1 received physiological saline. Groups 2–4 and 6 received single intraperitoneal (i.p) administration of 1.5 mg/kg body weight of CdCl2 (i.p) (Day 1). Groups 3–4 and 6 were posttreated with 15 mg/kg body weight of MO11, 15 mg/kg body weight of MO11 +7 mg/kg body weight of MS06, and 3.35 mg/kg body weight of doxorubicin, respectively (days: 1–17). Group 5 received only olive oil dose (vehicle), respectively (days: 1–17). Kidney histopathology (hematoxylin and eosin technique) and enzyme-linked immunosorbent assay concentrations of biomarkers of proliferation (Ki67) and apoptosis (p53) in kidney homogenates of rats of Groups 1–6 were evaluated. Results: Histopathological analyses showed normal kidney histology in the rats of Groups 1–6. Posttreatments of CdCl2-induced renotoxicity with MO11, MO11+MS06, and doxorubicin resulted in downregulations of Ki67 and p53 in Groups 3, 4, and 6 as compared with Group 2. Conclusion: MO11 and MS06 possess renoprotective, anti-proliferation, and anti-apoptosis potentials.

MO11 and MS06 ameliorated cadmium chloride-induced neuro-inflammation, hyperplasia and apoptosis via NF-kB/ Caspase-3/p53 pathway and down-regulated sVEGFR in rats

Cadmium is a neurotoxin, carcinogen and a suspected agent in aetiology of Parkinson’s disease and Alzheimer’s disease (AD). Furthermore, upregulations of Caspase-3 and p53 were reported in brains of AD patients. This study evaluated the neuroprotective potentials of MO11 (isolated from Moringa oleifera leaves) and MS06 (isolated from Musa sapientum suckers) in Cadmium Chloride (CdCl)-induced neurotoxicity in the cerebrum of rats. Twenty-eight adult male wistar rats (average weight of 155 g) were randomly divided into 7 groups (n = 4). Group 1 received physiological saline. Groups 2-4 and 7 received single 1.5 mg/Kg bodyweight of CdCl (i.p.) (Day 1). Groups 3-4 and 7 were post-treated with 15 mg/Kg bodyweight of MO11, 15 mg/Kg bodyweight of MO11 + 7 mg/Kg bodyweight of MSF1 and 3.35 mg/Kg bodyweight of Doxorubicin respectively (Days 1-17). Groups 5-6 received only MO11 and Vegetable Oil (vehicle) respectively (Days 1-17). Cerebral histopathology (Cresyl Fast Violet method) was evaluated in rats. ELISA evaluations of biomarkers of pro-inflammation (IL-1β, IL-6, IL-8 and NF-kB), anti-inflammation (IL-4 and IL- 10), apoptosis (Caspase-3 and p53), proliferation (Ki67) and angiogenesis (sVEGFR) in cerebral homogenates of rats were also conducted. Histopathological evaluations showed a high number of chromatolytic cells in Group 2, compared with Groups 1 and 3-7. Post-treatments of CdCl-induced neurotoxicity with MO11 and MS06 resulted in decreased levels of IL-1β, IL-6, IL-8, NF-kB, Caspase-3, Ki67, p53 and sVEGFR, but increased levels of IL-4 and IL-10 in Groups 3-4, compared with Group 2. Therefore, MO11 and MS06 possess neuroprotective, neuroregenerative, anti-AD, anti-inflammatory and anticancer potentials. Key words: Cadmium – Neurotoxicity – Alzheimer’s disease – Moringa oleifera – Musa sapientum – Neuroprotection – Neuroregeneration

Dietary Impacts on Changes in Diversity and Abundance of the Murine Microbiome During Progression and Treatment of Cancer

The microbiome has been recognized as being highly impactful for cancer outcomes, both with respect to the diversity and composition of the microbial population, as well as overall abundance. Presence or absence of certain microbial species has been correlated to improved cancer outcomes, in concert with specific treatments. However, little research has been performed to consider the reciprocal of this relationship: how different treatments, or the progression of disease, impact the microbiome. Further, though correlations have been demonstrated between dietary intake of both fats and carbohydrates and the composition and breadth of the microbiome, no studies have investigated the microbiome population as it is impacted by cancer and therapeutic treatments under different dietary regiments.This study aims to investigate how dietary patterns, in concert with progression of cancer and both surgical and therapeutic interventions, impact the diversity and abundance of the murine microbiome.A total of 116 c57BI/6 female mice (7‐8 weeks old) were randomized into four groups (n=29/group, each) one week post ovariectomy. Mice received a specific, semi‐purified diet consisting of A) low sucrose, high omega 3 fatty acid; B) low sucrose, low omega 3 fatty acid; C) high sucrose, high omega 3 fatty acid; or D) high sucrose, high omega 3 fatty acid. For high omega 3 fatty acid groups, 2% of daily calories were supplied to the mice as EPA and DHA in a 1.5:1 ratio. One week after implementation of diets all mice were inoculated with E0771 breast cancer cells. Twelve days following inoculation all mice were subject to lumpectomy. Eight days following, measurement procedures were repeated, as at baseline. Ten days following lumpectomy, half of the mice from each dietary cohort were treated with saline, while the other half were treated with a chemotherapeutic agent (9 mg/kg body weight doxorubicin and 90 mg/kg body weight cyclophosphamide). Six days later, the experiment ended, and mice were sacrificed following IACUC guidelines. Fecal samples, which had been collected at each time point noted above, were processed using QIAmp® PowerFecal® DNA isolation kit and were sent to MCIC (OSU Wooster Campus) for 16S ribosomal genetic profiling. A genomic library was generated, using previously validated primers for the V4 region. FASTQ files were filtered, trimmed, dereplicated, and denoised. Cleaned FASTQ files were then used to infer ASVs.Over the progression of cancer, there has been a consistent decrease in the alpha diversity of the microbiome. The effect of diet was mitigated by introduction of chemotherapeutic agents, though the significance of this effect is yet to be determined. While the analysis is still ongoing, it has been determined that there is a clear dietary effect which interacts with abundance. Multiple ASVs have been shown to be positively associated with high fat consumption, though inverse effects, as well as timepoint and treatment effects, have also been noted. Akkermansia muciniphila was a highly present bacterial species in all treatments, despite it usually being noted only as a minor resident of the gut.

Ameliorative effects of aqueous seed-extract of Dacryodes edulis on doxorubicin-induced cardiac tissue damage in albino rats

Ameliorative effects of aqueous seed extract of D acryodes edulis on doxorubicininduced cardiac tissue damage in albino rats were investigated. The animals were divided into groups and fed for 14 days to acclimatize. A single dose of 15 mg/kg body weight doxorubicin was given intraperitoneally to each group except the control group. After 48 hours, two animals were randomly selected from each group and sacrificed under ethylether anesthesia, to harvest their hearts for histological studies. Subsequently, groups 1 and 2 were given normal saline, while groups 3 and 4 were treated with 25 and 100 mg/kg body weight of aspirin and vitamin C respectively. Groups 5-8 received different doses of aqueous seed extract (200, 400, 600, and 800 mg/kg body weight). Treatments lasted for 21 days and the rats were sacrificed under anesthesia, and their hearts harvested and fixed in 10% formol saline for examination. The photomicrograph revealed severe and focal loss of cardiac fiber, intra-myocardial hemorrhages, fragmentation of cardiac muscle, and disorganization of histoarchitecture in the induced but untreated animal groups. Micrographs showed significant ameliorative effects of the extract in a dose-dependent way and healing effects of the standard drugs. These results showed that aqueous seed extract of Dacryodes edulis exhibits therapeutic potentials for cardiac disorders.

Empagliflozin Significantly Prevents the Doxorubicin-induced Acute Cardiotoxicity via Non-antioxidant Pathways.

Empagliflozin (EMPA) is a SGLT-2 inhibitor that has positive effects on cardiovascular outcomes. In this study, we aim to evaluate the possible protective effects of EMPA against doxorubicin (DOX)-inducedacute cardiotoxicity. Non-diabetic Sprague-Dawley rats were randomized into four groups. The control group received serum physiologic (1ml), the EMPA group received EMPA, the DOX group was administered cumulatively 18mg/kg body weight DOX. The DOX+EMPA group was administered DOX and EMPA. In the DOX group, LVDED (P < 0.05) and LVSED (P < 0.01), QTc interval (P < 0.001), the ratio of karyolysis and karyorrhexis (P < 0.001) and infiltrative cell proliferation (P < 0.001) were found to be higher than; EF, FS and normal cell morphology were lower than the control group (P < 0.001). In the DOX+EMPA group, LVEDD (P < 0.05) and LVESD (P < 0.01) values, QTc interval (P < 0.001), karyolysis and karyorrhexis ratios (P < 0.001) and infiltrative cell proliferation were lower (P < 0.01); normal cell morphology and EF were higher compared to the DOX group (P < 0.001). Our results showed that empagliflozin significantly ameliorated DOX-induced acutecardiotoxicity.

The role of exogenous epidermal growth factor on Ki-67 proliferation marker expression in the submandibular salivary gland of albino rats receiving doxorubicin

Background: This study was conducted to evaluate the role of exogenous epidermal growth factor (EGF) injection on the Ki-67 immuno-expression in submandibular salivary gland tissue of rats receiving doxorubicin (DXR). Methods: A total of 21 two-month-old male albino rats, of 200 g body weight, were divided into three groups: control group; DXR group, the rats received 20 mg/kg body weight DXR as a single intra peritoneal injection; DXR+EGF group, the rats received the same dose of DXR and on the next day they were injected intraperitoneally with 10 µg/kg body weight of EGF daily for one week. Histological sections and immunohistochemical expression of Ki67 sections were examined using a ZEISS Primo Star light microscopy and images taken using Tucsen IS 1000 10.0MP Camera. Results: Ki-67 expression was significantly increased in submandibular salivary glands of rats after DXR injection. However, Ki-67 expression in the glandular tissue was restored to normal levels after EGF injection. Conclusions: EGF preserved glandular architecture after DXR injection and maintained Ki-67 immune-expression within the glandular tissue near to the normal level.

The role of exogenous epidermal growth factor on Ki-67 proliferation marker expression in the submandibular salivary gland of albino rats receiving doxorubicin.

Background: This study was conducted to evaluate the role of exogenous epidermal growth factor (EGF) injection on the Ki-67 immuno-expression in submandibular salivary gland tissue of rats receiving doxorubicin (DXR). Methods: A total of 21 two-month-old male albino rats, of 200 g body weight, were divided into three groups: control group; DXR group, the rats received 20 mg/kg body weight DXR as a single intra peritoneal injection; DXR+EGF group, the rats received the same dose of DXR and on the next day they were injected intraperitoneally with 10 µg/kg body weight of EGF daily for one week. Histological sections and immunohistochemical expression of Ki67 sections were examined using a ZEISS Primo Star light microscopy and images taken using Tucsen IS 1000 10.0MP Camera. Results: Ki-67 expression was significantly increased in submandibular salivary glands of rats after DXR injection. However, Ki-67 expression in the glandular tissue was restored to normal levels after EGF injection. Conclusions: EGF preserved glandular architecture after DXR injection and maintained Ki-67 immune-expression within the glandular tissue near to the normal level.

The Effect of EGF on VEGF expression on Submandibular Salivary Gland of Albino Rats Receiving Doxorubicin

Background: Vascular endothelial growth factor (VEGF) has two prominent biological effects of inducing mitogenesis and migration of vascular endothelial cells and to produce permeability on the microvasculature. Epidermal growth factor (EGF), known by its mitogenic activity on different types of cells, could induce the proliferation and differentiation of the epithelial cells and stimulate its regeneration. Doxorubicin (DXR) is a widely used anticancer drug and is one of most commonly used chemotherapeutic drugs, however it may cause some serious complications such as toxicity in various tissues in the body.Aims: The present study aims to investigate the effect of EGF on the VEGF immunoexpression in submandibular salivary gland tissue of rats receiving Doxorubicin (DXR).Methods and Material: 30 male Albino rats, two months old and weighing 200-250 gm body weight, were divided equally into three groups as follows: Group I (control group). Group II: rats received 20 mg/kg body weight DXR as a single intra peritoneal injection. Whereas, group III: rats received the same dose of DXR and on the next day they were injected intraperitoneally with EGF in a daily dose of 10μg/kg body weight for 7 consecutive days.Submandibular salivary glands were dissected out and processed for histological investigation and immunohistochemical localization of VEGF in the glandular tissue.Statistical analysis used: ANOVA was used to compare the mean area percentage of VEGF immunostaining among the specimens of different groups followed by Tukey’s Multiple Comparison Test.Results: VEGF expression in submandibular salivary glands of rats significantly decreased after DXR injection. However, daily intraperitoneal injections of EGF restored normal levels of VEGF expression in the glandular tissue.Conclusions: EGF preserved glandular architecture after DXR injection and consequently the immunohistochemical expression of VEGF in the glands to approximately the normal level.

Ameliorative Effect of Trehalose on Liver Due to Doxorubicin-Induced Cardiomyopathy in Mice

Doxorubicin (DOX) is one of the most efficient anticancer chemotherapeutic drugs. However, its use is limited due to the induction of irreversible dilated cardiomyopathy and hepatotoxicity. The present study aimed to evaluate the hepatoprotective effect of trehalose (TRE) against DOX –induced cardiomyopathy(DIC). Mice were divided into five treated groups: Control group given saline, DOX group (2mg/kg body weight three times per week for three weeks day after day), TRE group (200µg/mouse three times per week for three weeks day after day), DOX+TRE cotreatment group (animals were co-administered 2mg/kg body weight of DOX with 200µg/mouse TRE by the same time), and DOX+TRE post treatment group (animals received 2mg/kg body weight DOX followed by treatment with 200µg/mouse TRE after 18 days). The obtained results indicated that DOX-treatment resulted in a decrease in body and liver weight ,and relative weight of liver compared to the control group. In addition, DOX-treatment caused an increase in activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST),and in level of hepatic malondialdehyde (MDA) concentration. However, concentration of total thiols (T-thiol), total antioxidant capacity (TAC) as well as catalase (CAT) enzyme activity were reduced in DOX-treated mice. Furthermore, dramatic changes in the histological architecture of the liver were observed. On the other hand, an improvement in the activities of ALT,AST, and CAT as well as levels of hepatic MDA ,T-thiol and TAC were observed in animals administrated with TRE either alone or in combination with DOX in cotreatment and post treatment groups in comparison with the ones treated with DOX alone. Moreover, histopathological examination of liver tissues in mice co-treated with DOX and TRE showed a significant improvement in hepatic parenchyma as compared to mice treated with DOX alone.

Protection of Doxorubicin-Induced Biochemical Injury in the Rat Bone Marrow by a Dietary Bioflavonoid Naringin

Doxorubicin is a secondary metabolite isolated, from Streptomyces peucetius and has been used as a standard chemotherapeutic agent alone or in conjunction with other chemotherapeutic drugs to treat different types of malignancies. The use of doxorubicin associated with adverse toxic side effect on bone marrow heart, kidneys and liver in patients receiving its therapy Therefore, any agent that can reduce the toxicity of doxorubicin will be useful in clinical conditions. Naringin a dietary flavonoid synthesized by different citrus fruits has been investigated for its protective effect against the doxorubicin-induced biochemical stress in albino rat bone marrow administered with 2 mg/kg body weight of naringin or 5 mg/kg body weight of doxorubicin either alone or in combination with each other. The bone marrow was aspirated at ½, 1 and 2 h post-doxorubicin treatment and activities of glutathione-s-transferase, catalase and superoxide dismutase, and glutathione concentration and lipid peroxidation were measured. Administration of doxorubicin alone caused a time dependent but significant reduction in the activities of catalase and superoxide dismutase and glutathione concentration followed by increased lipid peroxidation at ½, 1 and 2 h post-doxorubicin treatment. The treatment of rats with naringin before doxorubicin administration significantly raised the activities of catalase and glutathione concentration followed by reduction in the lipid peroxidation in the rat bone marrow. Our study shows that naringin attenuated the doxorubicin-induced biochemical stress and may be a useful agent in reducing the toxicity of doxorubicin in patients.

Doxorubicin induced neuro- and cardiotoxicities in experimental rats: Protection against oxidative damage by Theobroma cacao Stem bark

80 rats, randomly selected, were divided into 3 treatment groups: pre-, co- and post-treatment; consisting of 6 sub-groups each (5 rats per sub-group): baseline, normal saline (2mL), α-lipoic acid (20mg/kg body weight), 200mg/kg, 400mg/kg or 800mg/kg body weight Theobroma cacao stem bark aqueous extract (TCAE). All rats except for baseline group were intoxicated with 20mg/kg body weight doxorubicin (DOX) intraperitoneally. The animals in pre- or post-treatment group received a single dose of DOX (20mg/kg body weight) intraperitoneally 24h before or after 7 days’ oral administration with TCAE respectively while those in co-treatment group were co-administered 2.86mg/kg body weight of DOX with either normal saline, α- lipoic acid or TCAE orally for 7 days. Animals were sacrificed (pre- and post- treatment groups were sacrificed on the ninth day while the co-treatment group sacrificed on the 8th day). Brain and heart tissue samples were harvested for enzyme markers of toxicity, oxidative stress and histopathological examinations. DOX intoxication caused significant decrease in activities of LDH and ACP, and increase in γGT and ALP activities in brain tissues while causing a significant increase in LDH, ACP, γGT activities and decrease in ALP activity in the cardiac tissues. DOX intoxication caused a significant increase in concentrations of H2O2 generated, MDA and PC, XO, MPx and NOX activities with concomitant decrease in CAT, SOD, GPx and GST activities, and in concentrations of GSH, AsA and α-Toc in brain and cardiac tissues. Pre-, co- and post-treatment with TCAE at either 200mg/kg, 400mg/kg or 800mg/kg body weight significantly reversed the oxidative damage to the organs induced by DOX-intoxication. The result affirmed that T. cacao stem bark aqueous extract protected against DOX induced oxidative damage in brain and cardiac tissues of experimental rats.

Sex-related differential susceptibility to doxorubicin-induced cardiotoxicity in B6C3F1 mice

Sex is a risk factor for development of cardiotoxicity, induced by the anti-cancer drug, doxorubicin (DOX), in humans. To explore potential mechanisms underlying differential susceptibility to DOX between sexes, 8-week old male and female B6C3F1 mice were dosed with 3mg/kg body weight DOX or an equivalent volume of saline via tail vein once a week for 6, 7, 8, and 9 consecutive weeks, resulting in 18, 21, 24, and 27mg/kg cumulative DOX doses, respectively. At necropsy, one week after each consecutive final dose, the extent of myocardial injury was greater in male mice compared to females as indicated by higher plasma concentrations of cardiac troponin T at all cumulative DOX doses with statistically significant differences between sexes at the 21 and 24mg/kg cumulative doses. A greater susceptibility to DOX in male mice was further confirmed by the presence of cytoplasmic vacuolization in cardiomyocytes, with left atrium being more vulnerable to DOX cardiotoxicity. The number of TUNEL-positive cardiomyocytes was mostly higher in DOX-treated male mice compared to female counterparts, showing a statistically significant sex-related difference only in left atrium at 21mg/kg cumulative dose. DOX-treated male mice also had an increased number of γ-H2A.X-positive (measure of DNA double-strand breaks) cardiomyocytes compared to female counterparts with a significant sex effect in the ventricle at 27mg/kg cumulative dose and right atrium at 21 and 27mg/kg cumulative doses. This newly established mouse model provides a means to identify biomarkers and access potential mechanisms underlying sex-related differences in DOX-induced cardiotoxicity.

Effects of Aqueous Extract of Vigna unguiculata Seedlings Against Doxorubicin-Induced Cardiotoxicity and Kidney damage In Female Albino Rats

Doxorubicin is an anthracycline drug which is believed to cause immediate damage to myocardial cells by free radical generation in the cause of treatment of cancer. This study was however aimed to investigate the effects of the aqueous extract of the seedlings of Vigna unguiculata on heart, kidney as well as lipid profile disorders caused by this drug on female Wistar albino rats. Fifteen female Wistar albino rats were divided into three groups. Group 1 animals served as normal positive control; Group 2 animals served as negative control which were treated with 0.5mL of (20mg/kg body weight doxorubicin) while Group 3 animals were treated with 0.5mL each of 20mg/kg body weight doxorubicin and 10% aqueous extract of seedlings of Vigna unguiculata. Some enzyme markers and lipid contents were determined. The results of the study showed an increase in the activities of plasma ALP and AST after treatment with the drug except in the heart for AST which showed a significant reduction, while treatment with the extract brought about a decrease in the plasma and the organs except for kidney AST. The ALT on the other hand showed slight increase in the plasma with a decrease in the kidney and heart after treatment with the drug as the treatment with the extract tend to restore it to the control in both cases, there was increased plasma and kidney but reduced heart HDL-C after treatment with the drug which was observed to be restored to control after treatment with extract in both situations. The triglyceride and total cholesterol did not show similar trend in the plasma and the studied organs. The LDL-C was also observed to be increased in both plasma and organs after the treatment with the drug which later reduced significantly towards the control after the administration of the sprout extract. The present study has shown that the doxorubicin has damaging effects on both kidney and heart tissues while the sprouts extract produce a restoration to the normal in both organs.

Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR.