BACKGROUND: Recent discoveries in cancer therapeutics have proven combination therapies more effective than individual drugs. This study describes the efficacy of the combination of Cinnamomum zeylanicum and doxorubicin against benzene-induced leukemia. METHODS AND RESULTS: Brine shrimp assay was used to assess the cytotoxicity of C. zeylanicum, doxorubicin and their combination. After AML induction in Sprague Dawley rats, the same drugs were given to rat groups. Changes in organ weight, haematological profile, and hepatic enzymes were determined. Real-time PCR was used to elucidate the effect on the expression of STMN1, GAPDH, P53 and various TRAIL and NF-kappaB components. C. zeylanicum reduced the cytotoxicity of doxorubicin. The combination treatment showed better anti-leukemic results than any of the individual drugs as evident from STMN1 expression (p < 0.001). It was particularly effective in reducing total white blood cell counts and recovering lymphocytes, monocytes and eosinophils along with hepatic enzymes ALT and AST (p < 0.001). All doses recovered relative organ weights and improved blood parameters. The combination therapy was particularly effective in inducing apoptosis, inhibition of proliferation marker GAPDH (p < 0.001) and NF-kappaB pathway components Rel-A (p < 0.001) and Rel-B (p < 0.01). Expressions of TRAIL components c-FLIP (p < 0.001), TRAIL ligand (p < 0.001) and caspase 8 (p < 0.01) were also altered. CONCLUSION: Cinnamomum zeylanicum in combination with doxorubicin helps to counter benzene-induced cellular and hepatic toxicity and improves haematological profile. The anti-leukemic effects are potentially due to inhibition of GAPDH and NF-kappa B pathway, and through regulation of TRAIL pathway. Our data suggests the use of C. zeylanicum with doxorubicin to improve anti-leukemic therapeutic regimes.

Department of Biochemistry Quaid i Azam University Islamabad 45320 Pakistan

Department of Diet and Nutritional Sciences Ibadat International University Islamabad Pakistan

Department of Histology and Embryology Faculty of Medicine Masaryk University Brno Czech Republic

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$a Bukhari, Sidra $u Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan $1 https://orcid.org/http://orcid.org/0000000193085442

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$a Combined efficacy of Cinnamomum zeylanicum and doxorubicin against leukemia through regulation of TRAIL and NF-kappa B pathways in rat model / $c S. Bukhari, MH. Siddique, A. Naeem, I. Khan, Z. Ali, A. Essa, F. Fazal, RA. Anis, L. Moran, A. Sultan, I. Murtaza, P. Vanhara, M. Anees

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$a BACKGROUND: Recent discoveries in cancer therapeutics have proven combination therapies more effective than individual drugs. This study describes the efficacy of the combination of Cinnamomum zeylanicum and doxorubicin against benzene-induced leukemia. METHODS AND RESULTS: Brine shrimp assay was used to assess the cytotoxicity of C. zeylanicum, doxorubicin and their combination. After AML induction in Sprague Dawley rats, the same drugs were given to rat groups. Changes in organ weight, haematological profile, and hepatic enzymes were determined. Real-time PCR was used to elucidate the effect on the expression of STMN1, GAPDH, P53 and various TRAIL and NF-kappaB components. C. zeylanicum reduced the cytotoxicity of doxorubicin. The combination treatment showed better anti-leukemic results than any of the individual drugs as evident from STMN1 expression (p < 0.001). It was particularly effective in reducing total white blood cell counts and recovering lymphocytes, monocytes and eosinophils along with hepatic enzymes ALT and AST (p < 0.001). All doses recovered relative organ weights and improved blood parameters. The combination therapy was particularly effective in inducing apoptosis, inhibition of proliferation marker GAPDH (p < 0.001) and NF-kappaB pathway components Rel-A (p < 0.001) and Rel-B (p < 0.01). Expressions of TRAIL components c-FLIP (p < 0.001), TRAIL ligand (p < 0.001) and caspase 8 (p < 0.01) were also altered. CONCLUSION: Cinnamomum zeylanicum in combination with doxorubicin helps to counter benzene-induced cellular and hepatic toxicity and improves haematological profile. The anti-leukemic effects are potentially due to inhibition of GAPDH and NF-kappa B pathway, and through regulation of TRAIL pathway. Our data suggests the use of C. zeylanicum with doxorubicin to improve anti-leukemic therapeutic regimes.

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$a Siddique, Muhammad Hamid $u Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan $1 https://orcid.org/http://orcid.org/0000000262209550

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$a Naeem, Anum $u Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan $1 https://orcid.org/http://orcid.org/0000000185722464

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$a Khan, InamUllah $u Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan $1 https://orcid.org/http://orcid.org/0000000187195020

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$a Ali, Zain $u Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan $1 https://orcid.org/http://orcid.org/0000000155791127

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$a Essa, Asiya $u Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan $1 https://orcid.org/http://orcid.org/0000000160133815

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$a Fazal, Falak $u Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan

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$a Anis, Riffat Aysha $u Department of Diet and Nutritional Sciences, Ibadat International University, Islamabad, Pakistan

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$a Sultan, Aneesa $u Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan

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$a Vanhara, Petr $u Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic

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$a Anees, Mariam $u Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan. mariam@qau.edu.pk $1 https://orcid.org/http://orcid.org/0000000190494718

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