Natural Products for Treatment of Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3′ sequences from c-Abelson (abl) protooncogene on chromosome 9 with 5′ sequence of truncated break point cluster region (bcr) to chromosome 22. The fusion gene product BCR-ABL, a functional oncoprotein p210, is a constitutively activated tyrosine kinase that activates several cell proliferative signaling pathways. BCR-ABL-specific tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib and ponatinib potently inhibit CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Natural products are chemical compounds or substances produced by living organisms. They are becoming an important research area for cancer drug discovery due to their low toxicity and cost-effectiveness. Several lines of evidence show that many NPs such as alkaloids, flavonoids, terpenoids, polyketides, lignans and saponins inhibit CML cell proliferation and induce apoptosis. NPs not only differentiate CML cells into monocyte/erythroid lineage but also can reverse the multi-drug resistance (MDR) in CML cells. In this chapter, we review the anti-CML activity of various NPs

EVALUATION OF ANTI-CML ACTIVITY OF METHANOL AND AQUEOUS EXTRACTS OF BENKARA MALABARICA (LAM.) TIRVENG PLANT LEAVES

Objective: To investigate the phytoconstituents and in vitro cytotoxicity of methanol (MeOH) and aqueous (AQE) extracts of Benkara malabarica (Lam.) Triveng (BM) plant leaves.Methods: Gas chromatography-mass spectrometry (GC MS) was carried out to disclose the principal phytoconstituents present in MeOH and AQE extracts of BM. In vitro cytotoxicity of BM extracts were determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Acridine orange (AO)/ethidium bromide (EB) and 4', 6-diamidino-2-phenylindole (DAPI) staining were performed to visualize morphological changes upon treatment of BM extracts. Fluorescence-activated cell sorting (FACS) was carried out to determine the apoptosis and cell cycle arrestability of BM extracts.Results: GC MS analysis reported the presence of nine phytoconstituents in MeOH and AQE extracts of BM. The IC50 of BM MeOH, AQE extracts treated K562 cells were 49.78±1.697, 15.47±1.19 µg/ml for 48 h and found to be statistically significant (p<0.001). AO/EB and DAPI staining results anticipated the induction of apoptosis and DNA fragmentation upon treatment of BM extracts. FACS analysis revealed the SubG0 cell populations increased in K562 cells treated by BM MeOH (18.15) and AQE (51.26) extracts.Conclusion: The results of the present study uncovered that the BM AQE extract was more potent in inhibiting K562 cell proliferation through cell cycle arrest and apoptosis compared to the MeOH extract of BM.Â

GC MS AND ELEMENTAL ANALYSIS OF CINNAMOMUM TAMALA

Objective: To investigate the phytoconstituents and elements present in hexane (HEX), dichloromethane (DCM) and methanol (MET) extracts of Cinnamomum tamala (CT).Methods: Gas chromatography–mass spectrometry (GC-MS) was carried out to determine the principal constituents present in HEX, DCM and MET extracts of CT. Elemental analysis of CT was carried out by X–Ray Fluorescence (XRF) spectrophotometer analysis.Results: GC-MS analysis showed the presence of various compounds in HEX, DCM and MET extracts of CT. Eugenol was found to be the major compound in HEX and DCM extracts of CT. 2 compounds namely 2,6,10-trimethyl-12-oxatricyclo[7.3.0.0{1,6}]tridec-2-ene, Hexahydropyridine,4-[4,5-dimethoxyphenyl]-in HEX extract and 3 compounds in DCM extract namely 6á,19-CycloAndrost-4-ene-3,17-dione, 2,5-chloro-3β-hydroxy-6β-nitro-5α-androstan-17-one, Aceticacid,10,13-dimethyl-2-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H cyclopenta [a]phenanthren-17-ylester are newly reported. XRF analysis revealed the presence of various elements in CT. Out of these; calcium and potassium were found to be major elements, whereas titanium was found to be a minor element.Conclusions: The results of the present study demonstrate the presence of 31 various important phytoconstituents in HEX, DCM and MET extracts of CT and presence of 13 elements in CT. Â

Proapoptotic, Anti-Cell Proliferative, Anti-Inflammatory And Antiangiogenic Potential Of Carnosic Acid During 7,12 Dimethylbenz[A]Anthracene-Induced Hamster Buccal Pouch Carcinogenesis

The present study has investigated the modulating effect of carnosic acid on the expression pattern of cell proliferative (proliferating cell nuclear antigen (PCNA) cyclin D1 and a transcription factor c-fos), apoptotic (p53, Bcl-2, Bax caspase -3 and 9), inflammatory (Nuclear factor kappa B (NFκB) and cyclooxygenase-2 (COX- 2) and angiogenic (vascular endothelial growth factor (VEGF) markers during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Oral tumors were developed in the hamsters buccal pouches by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. Hundred per cent tumour formation (well-differentiated squamous cell carcinoma) accompanied by deregulation in the above mentioned molecular markers was noticed in hamsters treated with DMBA alone (tumour bearing hamsters). Oral administration of carnosic acid at dose of 10mg/kg bw to hamsters treated with DMBA not only completely prevented the tumour formation, but also corrected the abnormalities in the expression pattern of molecular markers. The present study suggests that carnosic acid might have inhibited the tumour formation by exerting anti-cell-proliferative, anti-inflammatory, anti-angiogenic and apoptotic potential during DMBA-induced hamster buccal pouch carcinogenesis

Proapoptotic, anti-cell proliferative, anti-inflammatory and antiangiogenic potential of carnosic acid during 7,12 dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis

ERRATUMRajasekaran et al., Afr., J. Tradit Complement Altern Med. 2013; 10(1): 102–112Published online 2012 Oct 1.doi: 10.4314/ajtcam.v10i1.1

Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl

<p>Abstract</p> <p>Background</p> <p>The proto-oncogene, c-Abl encodes a ubiquitously expressed tyrosine kinase that critically governs the cell death response induced by genotoxic agents such as ionizing radiation and cisplatin. The catalytic function of Abl, which is essential for executing DNA damage response (DDR), is normally tightly regulated but upregulated several folds upon IR exposure due to ATM-mediated phosphorylation on S465. However, the mechanism/s leading to activation of Abl's apoptotic activity is currently unknown.</p> <p>Results</p> <p>We investigated the role of acetyl modification in regulating apoptotic activity of Abl and the results showed that DNA strand break-inducing agents, ionizing radiation and bleomycin induced Abl acetylation. Using mass spectrophotometry and site-specific acetyl antibody, we identified Abl K921, located in the DNA binding domain, and conforming to one of the lysine residue in the consensus acetylation motif (<b>K</b>XXK--X3-5--SGS) is acetylated following DNA damage. We further observed that the S465 phosphorylated Abl is acetyl modified during DNA damage. Signifying the modification, cells expressing the non acetylatable K921R mutant displayed attenuated apoptosis compared to wild-type in response to IR or bleomycin treatment. WT-Abl induced apoptosis irrespective of new protein synthesis. Furthermore, upon γ-irradiation K921R-Abl displayed reduced chromatin binding compared to wild type. Finally, loss of Abl K921 acetylation in Tip60-knocked down cells and co-precipitation of Abl with Tip60 in DNA damaged cells identified Tip60 as an Abl acetylase.</p> <p>Conclusion</p> <p>Collective data showed that DNA damage-induced K921 Abl acetylation, mediated by Tip60, stimulates transcriptional-independent apoptotic activity and chromatin-associative property thereby defining a new regulatory mechanism governing Abl's DDR function.</p

PROAPOPTOTIC, ANTI-CELL PROLIFERATIVE, ANTI-INFLAMMATORY AND ANTI-ANGIOGENIC POTENTIAL OF CARNOSIC ACID DURING 7,12 DIMETHYLBENZ[A]ANTHRACENE-INDUCED HAMSTER BUCCAL POUCH CARCINOGENESIS.

The present study has investigated the modulating effect of carnosic acid on the expression pattern of cell proliferative (proliferating cell nuclear antigen (PCNA) cyclin D1 and a transcription factor c-fos), apoptotic (p53, Bcl-2, Bax caspase -3 and 9), inflammatory (Nuclear factor kappa B (NFκB) and cyclooxygenase-2 (COX- 2) and angiogenic (vascular endothelial growth factor (VEGF) markers during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Oral tumors were developed in the hamsters buccal pouches by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. Hundred per cent tumour formation (well-differentiated squamous cell carcinoma) accompanied by deregulation in the above mentioned molecular markers was noticed in hamsters treated with DMBA alone (tumour bearing hamsters). Oral administration of carnosic acid at dose of 10mg/kg bw to hamsters treated with DMBA not only completely prevented the tumour formation, but also corrected the abnormalities in the expression pattern of molecular markers. The present study suggests that carnosic acid might have inhibited the tumour formation by exerting anti-cell-proliferative, anti-inflammatory, anti-angiogenic and apoptotic potential during DMBA-induced hamster buccal pouch carcinogenesis

Acid Catalysed Prototropy of Substituted Acetonaphthones- Kinetics of Perchloric Acid Catalysed Bromination & Phenyl Iodosoacetate Oxidation

1008-101

Spectrophotometric Determination of Dissociation Constants of 2,4-Dinitrophenylhydrazones of Substituted Acetonaphthones

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