Journal of Receptors and Signal Transduction, Jul 4, 2018
De novo lipogenesis (DNL) by upregulation of fatty acid synthase (FASN) is an important metabolic... more De novo lipogenesis (DNL) by upregulation of fatty acid synthase (FASN) is an important metabolic alteration of cancer cells. FASN is over-expressed in several cancers and is often associated with a high risk of recurrence and poor prognosis. Differential expression of FASN in cancer cells and their normal counterparts leads to the impression that FASN can be an attractive druggable target in cancer therapy. Present study focuses on identification of inhibitors against FASN ketoacyl synthase (KS) domain from Asinex Biodesign compound database using in silico tools. Virtual screening resulted in the identification of two hit compounds BDD27845077 and BDD27845082 with a common core structure. Molecular Docking studies showed that BDD27845077 and BDD27845082 bind at the substrate entry channel of KS domain with GScore -12.03 kcal/mol and -12.29 kcal/mol respectively. Molecular dynamics (MD) simulation of the protein-ligand complexes shows the binding stability of ligands with FASN-KS. In vitro validation of BDD27845082 demonstrated that the compound possesses antiproliferative activity in a panel of human cancer cell lines including MDA-MB-231 (breast cancer), HCT-116 (colon cancer) and HeLa (cervical cancer) with maximum sensitivity against HCT-116 (IC 50 = 25 µM). The study put forward two lead compounds against FASN with favorable pharmacokinetic profile as indicated by virtual screening tools for the development of cancer chemotherapeutics.
Selenium (Se) is incorporated into the body via the selenocysteine (Sec) biosynthesis pathway, wh... more Selenium (Se) is incorporated into the body via the selenocysteine (Sec) biosynthesis pathway, which is critical in the synthesis of selenoproteins, such as glutathione peroxidases and thioredoxin reductases. Selenoproteins, which play a key role in several biological processes, including ferroptosis, drug resistance, endoplasmic reticulum stress, and epigenetic processes, are guided by Se uptake. In this review, we critically analyze the molecular mechanisms of Se metabolism and its potential as a therapeutic target for cancer. Sec insertion sequence binding protein 2 (SECISBP2), which is a positive regulator for the expression of selenoproteins, would be a novel prognostic predictor and an alternate target for cancer. We highlight strategies that attempt to develop a novel Se metabolism‐based approach to uncover a new metabolic drug target for cancer therapy. Moreover, we expect extensive clinical use of SECISBP2 as a specific biomarker in cancer therapy in the near future. Of not...
Exploration of targeted anti-tumor therapy, Apr 24, 2023
Aim: This study was designed to investigate the anticancer efficacy of the organic leaf extracts ... more Aim: This study was designed to investigate the anticancer efficacy of the organic leaf extracts of the plant, Plectranthus vettiveroides (P. vettiveroides), and to analyze the molecular mechanism of the anticancer activity. Methods: The leaf extracts were prepared by polarity-graded serial extraction of the dried leaf powder. The cytotoxic effect of the extracts was analyzed by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The most active ethyl acetate extract was subjected to bioactivity-guided fractionation by column chromatography, which yielded a cytotoxic fraction designated as the P. vettiveroides fraction (PVF). The anticancer property of PVF was confirmed further by clonogenic assay. The mechanism of PVF-induced cell death was analyzed by flow cytometry and fluorescence microscopy. Additionally, the effects of PVF on apoptotic and cell survival pathways were analyzed using western immunoblot analysis. Results: A bioactive fraction PVF, was isolated from the ethyl acetate leaf extract. PVF showed significant anticancer activity against colon cancer cells, whilst normal cells were comparatively less affected. PVF induced strong apoptotic stimuli in colorectal carcinoma cell line HCT116, involving both extrinsic and intrinsic pathways. Investigation into the molecular mechanism of anticancer activity of PVF in HCT116 cells revealed that the fraction activates the pro-apoptotic pathway via tumor suppressor protein 53 (p53) and inhibits the anti-apoptotic pathway by regulating phosphatidylinositol 3-kinase (PI3K) signaling. Conclusions: The findings of this study demonstrate, with mechanism-based evidence, the chemotherapeutic potential of a bioactive fraction PVF, derived from the leaves of the medicinal plant P. vettiveroides against colon cancer.
We report the isolation and characterization of four compounds from a cytotoxic fraction F-17, is... more We report the isolation and characterization of four compounds from a cytotoxic fraction F-17, isolated from the DCM extract of C. odorata by bioactivity guided fractionation.
The alkaloids, 6-acetonyldihydrochelerythrin 1 and arnottianamide 2 have been isolated for the fi... more The alkaloids, 6-acetonyldihydrochelerythrin 1 and arnottianamide 2 have been isolated for the first time from conical prickles on the stem bark of Zanthoxylum rhetsa (Roxb.) DC. These compounds have been investigated for their cytotoxicity against seven cancer cell lines of various origins. The compound 1 is proved to be more potent as an anticancer agent and is very specific to the colon cancer cell line, SW-480 and cervical cancer cell line, HeLa. Compound 2 is more active against breast cancer cell lines. The change in anticancer activity of 1 after conversion to 6-(2-hydoxypropyl)-dihydrochelerythrine 3 has also been evaluated and a decrease in activity is observed.
Essential oils, water and ethanol extracts of black pepper, ginger, turmeric, cinnamon, Garcinia ... more Essential oils, water and ethanol extracts of black pepper, ginger, turmeric, cinnamon, Garcinia indica, G. gummi-gutta, tamarind and curry leaves were examined for their antioxidant potential and cytotoxicity to cancer cell lines by in vitro methods. Essential oils of ginger, turmeric, cinnamon and curry leaf were highly cytotoxic, reducing cell viability to 14 to 30% of untreated control; water and ethanol extracts of G. indica, turmeric, cinnamon, tamarind and curry leaf were also cytotoxic, though to a lesser extent (27% to none); ethanol extracts displayed approximately 50% higher cytotoxicity than water extracts. Antioxidant potential of water and ethanol extracts were similar, and decreased after six months of storage in most extracts; most were superior to BHA and BHT. Antioxidant potential of ethanol was also greater than water extracts. Change in essential oil chemoprofile stored at 4°C for a year compared to fresh, most notably t-caryophyllene, is also reported here.
Abstract Natural products occupy a unique region of chemical space that overlaps extensively with... more Abstract Natural products occupy a unique region of chemical space that overlaps extensively with pharmaceuticals and is not found in synthetic chemical libraries. From ancient days onwards, Indian and Chinese medicine had made use of the anti-cancer properties of various plant and animal derived products. Nutraceuticals are naturally occurring non-toxic dietary compounds that can offer physiological benefits against chronic diseases. Majority of the well-known nutraceuticals are phytochemicals. Even though the mainstay for cancer treatment, currently available chemotherapy regimens fail to accomplish their maximum therapeutic efficacy due to the emergence of acquired and intrinsic chemoresistance. Recent studies have shown that nutraceuticals can influence various molecular signaling pathways leading to multistage carcinogenesis as well as chemoresistance. This chapter provides an overview on the relevance of various nutraceuticals in cancer treatment together with their usefulness as chemopreventives and chemosensitizers.
Biological Activity of 3,5-Dihydroxy-4-ethyl-trans-stilbene of the cell cycle, as resveratrol. Ou... more Biological Activity of 3,5-Dihydroxy-4-ethyl-trans-stilbene of the cell cycle, as resveratrol. Our results indicate that DETS is a powerful antioxidant, having anticancer efficacy comparable with that of resveratrol, and is a potential candidate to be explored by in vivo studies and in-depth mechanistic evaluation. To our knowledge, this is the first report on the antioxidant and anticancer properties of DETS.
The synthesis and cytotoxic activity studies of a new series of cyclic amine containing benzoxazo... more The synthesis and cytotoxic activity studies of a new series of cyclic amine containing benzoxazole and benzoxazolone derivatives are described. The 2-cyclic amine-1,3-benzoxazoles 5a–k, 5-chloro-3-(3-chloropropyl)-1,3-benzoxazol-2(3H)-one 8 and 3-[3-(cyclic amino)propyl]-1,3-benzoxazol-2(3H)-ones 9a–f were synthesized. The newly synthesized compounds with the influence of the presence of cyclic amine moiety in the benzoxazole scaffold have been evaluated with respect to their cytotoxic effect toward
The synthesis of a series of substituted hippuric acid (2-benzamidoacetic acid) derivatives conta... more The synthesis of a series of substituted hippuric acid (2-benzamidoacetic acid) derivatives containing arylsulfonylpiperazine nucleus (3a-j, 4a-j) is described. The compounds were synthesized by coupling hippuric/4-fluorohippuric acid with various arylsulfonylpiperazines using N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI). The structures of all the new compounds were confirmed by IR, NMR and MS spectral data. All the synthesized compounds have been evaluated for their in vitro cytotoxicity towards five human cancer cell lines of different origins viz. HeLa (Cervical), A549 (Lung), A375 (Skin), MD-AMB-231(Breast) and T98G (brain) and their IC50 values were determined. Among the compounds tested, 3b, 3d, 3g, 4c and 4e displayed significant cytotoxic activity (IC50 = 24.2-38.2 µM). T98G was the most sensitive cell line towards the compounds studied followed by HeLa, A375, A549 and MD-AMB-231.
3,5-Dihydroxy-4-isopropylstilbene is a natural phytoalexin and was first identified as bacterial ... more 3,5-Dihydroxy-4-isopropylstilbene is a natural phytoalexin and was first identified as bacterial secondary metabolites. The aim of this study is to investigate in vitro antioxidant and anticancer activity of 3,5-dihydroxy-4-isopropystilbene purified from the cell free culture filtrate of Bacillus sp. N strain associated with rhabditid entomopathogenic nematode. Antioxidant activity was evaluated by five separate methods: free radical scavenging, reducing power assay, chelating effects on ferrous ions, NBT superoxide radical scavenging assay and hydroxyl radical scavenging activity. The stilbene recorded powerful antioxidant activity at various antioxidant systems in vitro. The superoxide radical scavenging (92.1 %) and hydroxyl radical scavenging (83.4 %) activities of the stilbenes at 100 μg/ml were higher than the butylated hydroxyanisole, the known antioxidant agent. Anticancer activity of stilbene was tested against breast cancer (MDAM B-231), cervical cancer (HeLa), lung cancer (A 549), colon cancer (HTL 116) cell lines using MTT method. The induction of apoptosis was studied by morphological analysis, apoptotic cell staining, caspase 3 activation assay and cell cycle analysis using flow cytometry. Stilbene induced significant morphological changes and DNA fragmentation associated with apoptosis in HeLa cells. Acridine orange/ethidium bromide stained cells indicated apoptosis induction by stilbene. Up-regulation of caspase 3 activity was also found in cells treated with stilbene. Flow cytometry analysis showed an increase in the percentage of apoptotic cells in sub G0 phase (2.4 % in control plates to 11.4 % in 25 μg/ml of stilbene) confirming the stilbene induced apoptosis. The results of the present study showed that stilbene demonstrated a strong antioxidant and anticancer effects. These suggest that stilbene may be used as possible natural antioxidant and anticancer agents to control various human diseases.
We report mechanism-based evidence for the anticancer efficacy of a protein fraction, SF2 (Sesban... more We report mechanism-based evidence for the anticancer efficacy of a protein fraction, SF2 (Sesbania fraction 2) isolated from the flower of the medicinal plant, Sesbania grandiflora (S. grandiflora). The fraction was evaluated in two murine ascites tumour cell lines and human cancer cell lines of different origin for its anticancer effect. SF2 inhibited cell proliferation and induced apoptosis as demonstrated by DNA fragmentation and externalization of phosphatidyl serine in Daltons lymphoma ascites (DLA) and colon cancer cells (SW-480). Sensitivity to SF2 in these cells was associated with activation of caspases 3, 8 and 9, poly (ADP-ribose) polymerase cleavage and cytochrome C release which attests apoptosis induced cell death. Mechanistically, SF2 down-regulated phorbol myristate acetate (PMA) induced NF-B, a transcription factor which controls the expression of genes encoding proteins involved in cell regulation and growth control. Additionally, SF2 also down-regulated anti-apoptotic factors such as Bcl-2, p-Akt and cyclooxygenase-2 induced by the tumour promoter PMA suggestive of a possible explanation for its anticancer effect. In vivo studies using ascites and solid tumour models strongly support in vitro findings as SF2 administration increased the life span and decreased the tumour volume in mice bearing tumour. In vivo toxicological evaluation revealed the pharmacological safety of SF2 and may serve as a potential anticancer drug candidate.
Sorafenib is the sole FDA approved drug conventionally used for the treatment of advanced hepatoc... more Sorafenib is the sole FDA approved drug conventionally used for the treatment of advanced hepatocellular carcinoma (HCC). Despite of the beneficial use of sorafenib in the treatment of HCC, multidrug resistance still remains a challenge. HCC is inherently known as chemotherapy resistant tumor due to P-glycoprotein (P-gp)-mediated multidrug resistance. Methods: We studied the interaction energy of kaempferol with human multidrug resistance protein-1 (RCSB PDB ID: 2CBZ) using in silico method with the help of BIOVIA Discovery Studio. HepG2 and N1S1 liver cancer cell lines were treated in suitable cell culture media to evaluate the efficacy of kaempferol in chemo-sensitizing liver cancer cells towards the effect of sorafenib. Cell viability study was performed by MTT assay. Results: In silico analysis of kaempferol showed best docking score of 23.14 with Human Multi Drug Resistant Protein-1 (RCSB PDB ID: 2CBZ) compared with positive control verapamil. In in-vitro condition, combination of sub-toxic concentrations of both kaempferol and sorafenib produced 50% cytotoxicity with concentration of 2.5 µM each which indicates that kaempferol has the ability to reverse the MDR by decreasing the over-expression of P-gp. Conclusion: Kaempferol is able to sensitize the HepG2 and N1S1 against the sub-toxic concentration of sorafenib. Hence, we consider that the efficacy of sorafenib chemotherapy can be enhanced by the significant approach of combining the sub-toxic concentrations of sorafenib with kaempferol. Thus, kaempferol can be used as a better candidate molecule along with sorafenib for enhancing its efficacy, if validated through preclinical studies.
The idea and practice of developing or identifying compounds capable of eliminating the transform... more The idea and practice of developing or identifying compounds capable of eliminating the transformed cells or cancer cells without being nontoxic to their normal counterparts deserves much importance. Since ages, plants have been considered and proven to be repertoires of chemicals possessing immense therapeutic potential. A proportion of these plant-derived compounds or phytochemicals were shown to be highly competent anticancer agents besides being effective against many other diseases. Representative compounds of different classes of phytochemicals are in clinical use against cancer. In this chapter, we discuss the anticancer potential of two compounds: quercetin, a flavonoid and tryptanthrin, an indoloquinazoline alkaloid, and the mechanisms behind their cytotoxic effects on cancers of different origin. The chapter also gives a brief mention of their properties that make them effective against cancer.
Journal of Receptors and Signal Transduction, Jul 4, 2018
De novo lipogenesis (DNL) by upregulation of fatty acid synthase (FASN) is an important metabolic... more De novo lipogenesis (DNL) by upregulation of fatty acid synthase (FASN) is an important metabolic alteration of cancer cells. FASN is over-expressed in several cancers and is often associated with a high risk of recurrence and poor prognosis. Differential expression of FASN in cancer cells and their normal counterparts leads to the impression that FASN can be an attractive druggable target in cancer therapy. Present study focuses on identification of inhibitors against FASN ketoacyl synthase (KS) domain from Asinex Biodesign compound database using in silico tools. Virtual screening resulted in the identification of two hit compounds BDD27845077 and BDD27845082 with a common core structure. Molecular Docking studies showed that BDD27845077 and BDD27845082 bind at the substrate entry channel of KS domain with GScore -12.03 kcal/mol and -12.29 kcal/mol respectively. Molecular dynamics (MD) simulation of the protein-ligand complexes shows the binding stability of ligands with FASN-KS. In vitro validation of BDD27845082 demonstrated that the compound possesses antiproliferative activity in a panel of human cancer cell lines including MDA-MB-231 (breast cancer), HCT-116 (colon cancer) and HeLa (cervical cancer) with maximum sensitivity against HCT-116 (IC 50 = 25 µM). The study put forward two lead compounds against FASN with favorable pharmacokinetic profile as indicated by virtual screening tools for the development of cancer chemotherapeutics.
Selenium (Se) is incorporated into the body via the selenocysteine (Sec) biosynthesis pathway, wh... more Selenium (Se) is incorporated into the body via the selenocysteine (Sec) biosynthesis pathway, which is critical in the synthesis of selenoproteins, such as glutathione peroxidases and thioredoxin reductases. Selenoproteins, which play a key role in several biological processes, including ferroptosis, drug resistance, endoplasmic reticulum stress, and epigenetic processes, are guided by Se uptake. In this review, we critically analyze the molecular mechanisms of Se metabolism and its potential as a therapeutic target for cancer. Sec insertion sequence binding protein 2 (SECISBP2), which is a positive regulator for the expression of selenoproteins, would be a novel prognostic predictor and an alternate target for cancer. We highlight strategies that attempt to develop a novel Se metabolism‐based approach to uncover a new metabolic drug target for cancer therapy. Moreover, we expect extensive clinical use of SECISBP2 as a specific biomarker in cancer therapy in the near future. Of not...
Exploration of targeted anti-tumor therapy, Apr 24, 2023
Aim: This study was designed to investigate the anticancer efficacy of the organic leaf extracts ... more Aim: This study was designed to investigate the anticancer efficacy of the organic leaf extracts of the plant, Plectranthus vettiveroides (P. vettiveroides), and to analyze the molecular mechanism of the anticancer activity. Methods: The leaf extracts were prepared by polarity-graded serial extraction of the dried leaf powder. The cytotoxic effect of the extracts was analyzed by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The most active ethyl acetate extract was subjected to bioactivity-guided fractionation by column chromatography, which yielded a cytotoxic fraction designated as the P. vettiveroides fraction (PVF). The anticancer property of PVF was confirmed further by clonogenic assay. The mechanism of PVF-induced cell death was analyzed by flow cytometry and fluorescence microscopy. Additionally, the effects of PVF on apoptotic and cell survival pathways were analyzed using western immunoblot analysis. Results: A bioactive fraction PVF, was isolated from the ethyl acetate leaf extract. PVF showed significant anticancer activity against colon cancer cells, whilst normal cells were comparatively less affected. PVF induced strong apoptotic stimuli in colorectal carcinoma cell line HCT116, involving both extrinsic and intrinsic pathways. Investigation into the molecular mechanism of anticancer activity of PVF in HCT116 cells revealed that the fraction activates the pro-apoptotic pathway via tumor suppressor protein 53 (p53) and inhibits the anti-apoptotic pathway by regulating phosphatidylinositol 3-kinase (PI3K) signaling. Conclusions: The findings of this study demonstrate, with mechanism-based evidence, the chemotherapeutic potential of a bioactive fraction PVF, derived from the leaves of the medicinal plant P. vettiveroides against colon cancer.
We report the isolation and characterization of four compounds from a cytotoxic fraction F-17, is... more We report the isolation and characterization of four compounds from a cytotoxic fraction F-17, isolated from the DCM extract of C. odorata by bioactivity guided fractionation.
The alkaloids, 6-acetonyldihydrochelerythrin 1 and arnottianamide 2 have been isolated for the fi... more The alkaloids, 6-acetonyldihydrochelerythrin 1 and arnottianamide 2 have been isolated for the first time from conical prickles on the stem bark of Zanthoxylum rhetsa (Roxb.) DC. These compounds have been investigated for their cytotoxicity against seven cancer cell lines of various origins. The compound 1 is proved to be more potent as an anticancer agent and is very specific to the colon cancer cell line, SW-480 and cervical cancer cell line, HeLa. Compound 2 is more active against breast cancer cell lines. The change in anticancer activity of 1 after conversion to 6-(2-hydoxypropyl)-dihydrochelerythrine 3 has also been evaluated and a decrease in activity is observed.
Essential oils, water and ethanol extracts of black pepper, ginger, turmeric, cinnamon, Garcinia ... more Essential oils, water and ethanol extracts of black pepper, ginger, turmeric, cinnamon, Garcinia indica, G. gummi-gutta, tamarind and curry leaves were examined for their antioxidant potential and cytotoxicity to cancer cell lines by in vitro methods. Essential oils of ginger, turmeric, cinnamon and curry leaf were highly cytotoxic, reducing cell viability to 14 to 30% of untreated control; water and ethanol extracts of G. indica, turmeric, cinnamon, tamarind and curry leaf were also cytotoxic, though to a lesser extent (27% to none); ethanol extracts displayed approximately 50% higher cytotoxicity than water extracts. Antioxidant potential of water and ethanol extracts were similar, and decreased after six months of storage in most extracts; most were superior to BHA and BHT. Antioxidant potential of ethanol was also greater than water extracts. Change in essential oil chemoprofile stored at 4°C for a year compared to fresh, most notably t-caryophyllene, is also reported here.
Abstract Natural products occupy a unique region of chemical space that overlaps extensively with... more Abstract Natural products occupy a unique region of chemical space that overlaps extensively with pharmaceuticals and is not found in synthetic chemical libraries. From ancient days onwards, Indian and Chinese medicine had made use of the anti-cancer properties of various plant and animal derived products. Nutraceuticals are naturally occurring non-toxic dietary compounds that can offer physiological benefits against chronic diseases. Majority of the well-known nutraceuticals are phytochemicals. Even though the mainstay for cancer treatment, currently available chemotherapy regimens fail to accomplish their maximum therapeutic efficacy due to the emergence of acquired and intrinsic chemoresistance. Recent studies have shown that nutraceuticals can influence various molecular signaling pathways leading to multistage carcinogenesis as well as chemoresistance. This chapter provides an overview on the relevance of various nutraceuticals in cancer treatment together with their usefulness as chemopreventives and chemosensitizers.
Biological Activity of 3,5-Dihydroxy-4-ethyl-trans-stilbene of the cell cycle, as resveratrol. Ou... more Biological Activity of 3,5-Dihydroxy-4-ethyl-trans-stilbene of the cell cycle, as resveratrol. Our results indicate that DETS is a powerful antioxidant, having anticancer efficacy comparable with that of resveratrol, and is a potential candidate to be explored by in vivo studies and in-depth mechanistic evaluation. To our knowledge, this is the first report on the antioxidant and anticancer properties of DETS.
The synthesis and cytotoxic activity studies of a new series of cyclic amine containing benzoxazo... more The synthesis and cytotoxic activity studies of a new series of cyclic amine containing benzoxazole and benzoxazolone derivatives are described. The 2-cyclic amine-1,3-benzoxazoles 5a–k, 5-chloro-3-(3-chloropropyl)-1,3-benzoxazol-2(3H)-one 8 and 3-[3-(cyclic amino)propyl]-1,3-benzoxazol-2(3H)-ones 9a–f were synthesized. The newly synthesized compounds with the influence of the presence of cyclic amine moiety in the benzoxazole scaffold have been evaluated with respect to their cytotoxic effect toward
The synthesis of a series of substituted hippuric acid (2-benzamidoacetic acid) derivatives conta... more The synthesis of a series of substituted hippuric acid (2-benzamidoacetic acid) derivatives containing arylsulfonylpiperazine nucleus (3a-j, 4a-j) is described. The compounds were synthesized by coupling hippuric/4-fluorohippuric acid with various arylsulfonylpiperazines using N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI). The structures of all the new compounds were confirmed by IR, NMR and MS spectral data. All the synthesized compounds have been evaluated for their in vitro cytotoxicity towards five human cancer cell lines of different origins viz. HeLa (Cervical), A549 (Lung), A375 (Skin), MD-AMB-231(Breast) and T98G (brain) and their IC50 values were determined. Among the compounds tested, 3b, 3d, 3g, 4c and 4e displayed significant cytotoxic activity (IC50 = 24.2-38.2 µM). T98G was the most sensitive cell line towards the compounds studied followed by HeLa, A375, A549 and MD-AMB-231.
3,5-Dihydroxy-4-isopropylstilbene is a natural phytoalexin and was first identified as bacterial ... more 3,5-Dihydroxy-4-isopropylstilbene is a natural phytoalexin and was first identified as bacterial secondary metabolites. The aim of this study is to investigate in vitro antioxidant and anticancer activity of 3,5-dihydroxy-4-isopropystilbene purified from the cell free culture filtrate of Bacillus sp. N strain associated with rhabditid entomopathogenic nematode. Antioxidant activity was evaluated by five separate methods: free radical scavenging, reducing power assay, chelating effects on ferrous ions, NBT superoxide radical scavenging assay and hydroxyl radical scavenging activity. The stilbene recorded powerful antioxidant activity at various antioxidant systems in vitro. The superoxide radical scavenging (92.1 %) and hydroxyl radical scavenging (83.4 %) activities of the stilbenes at 100 μg/ml were higher than the butylated hydroxyanisole, the known antioxidant agent. Anticancer activity of stilbene was tested against breast cancer (MDAM B-231), cervical cancer (HeLa), lung cancer (A 549), colon cancer (HTL 116) cell lines using MTT method. The induction of apoptosis was studied by morphological analysis, apoptotic cell staining, caspase 3 activation assay and cell cycle analysis using flow cytometry. Stilbene induced significant morphological changes and DNA fragmentation associated with apoptosis in HeLa cells. Acridine orange/ethidium bromide stained cells indicated apoptosis induction by stilbene. Up-regulation of caspase 3 activity was also found in cells treated with stilbene. Flow cytometry analysis showed an increase in the percentage of apoptotic cells in sub G0 phase (2.4 % in control plates to 11.4 % in 25 μg/ml of stilbene) confirming the stilbene induced apoptosis. The results of the present study showed that stilbene demonstrated a strong antioxidant and anticancer effects. These suggest that stilbene may be used as possible natural antioxidant and anticancer agents to control various human diseases.
We report mechanism-based evidence for the anticancer efficacy of a protein fraction, SF2 (Sesban... more We report mechanism-based evidence for the anticancer efficacy of a protein fraction, SF2 (Sesbania fraction 2) isolated from the flower of the medicinal plant, Sesbania grandiflora (S. grandiflora). The fraction was evaluated in two murine ascites tumour cell lines and human cancer cell lines of different origin for its anticancer effect. SF2 inhibited cell proliferation and induced apoptosis as demonstrated by DNA fragmentation and externalization of phosphatidyl serine in Daltons lymphoma ascites (DLA) and colon cancer cells (SW-480). Sensitivity to SF2 in these cells was associated with activation of caspases 3, 8 and 9, poly (ADP-ribose) polymerase cleavage and cytochrome C release which attests apoptosis induced cell death. Mechanistically, SF2 down-regulated phorbol myristate acetate (PMA) induced NF-B, a transcription factor which controls the expression of genes encoding proteins involved in cell regulation and growth control. Additionally, SF2 also down-regulated anti-apoptotic factors such as Bcl-2, p-Akt and cyclooxygenase-2 induced by the tumour promoter PMA suggestive of a possible explanation for its anticancer effect. In vivo studies using ascites and solid tumour models strongly support in vitro findings as SF2 administration increased the life span and decreased the tumour volume in mice bearing tumour. In vivo toxicological evaluation revealed the pharmacological safety of SF2 and may serve as a potential anticancer drug candidate.
Sorafenib is the sole FDA approved drug conventionally used for the treatment of advanced hepatoc... more Sorafenib is the sole FDA approved drug conventionally used for the treatment of advanced hepatocellular carcinoma (HCC). Despite of the beneficial use of sorafenib in the treatment of HCC, multidrug resistance still remains a challenge. HCC is inherently known as chemotherapy resistant tumor due to P-glycoprotein (P-gp)-mediated multidrug resistance. Methods: We studied the interaction energy of kaempferol with human multidrug resistance protein-1 (RCSB PDB ID: 2CBZ) using in silico method with the help of BIOVIA Discovery Studio. HepG2 and N1S1 liver cancer cell lines were treated in suitable cell culture media to evaluate the efficacy of kaempferol in chemo-sensitizing liver cancer cells towards the effect of sorafenib. Cell viability study was performed by MTT assay. Results: In silico analysis of kaempferol showed best docking score of 23.14 with Human Multi Drug Resistant Protein-1 (RCSB PDB ID: 2CBZ) compared with positive control verapamil. In in-vitro condition, combination of sub-toxic concentrations of both kaempferol and sorafenib produced 50% cytotoxicity with concentration of 2.5 µM each which indicates that kaempferol has the ability to reverse the MDR by decreasing the over-expression of P-gp. Conclusion: Kaempferol is able to sensitize the HepG2 and N1S1 against the sub-toxic concentration of sorafenib. Hence, we consider that the efficacy of sorafenib chemotherapy can be enhanced by the significant approach of combining the sub-toxic concentrations of sorafenib with kaempferol. Thus, kaempferol can be used as a better candidate molecule along with sorafenib for enhancing its efficacy, if validated through preclinical studies.
The idea and practice of developing or identifying compounds capable of eliminating the transform... more The idea and practice of developing or identifying compounds capable of eliminating the transformed cells or cancer cells without being nontoxic to their normal counterparts deserves much importance. Since ages, plants have been considered and proven to be repertoires of chemicals possessing immense therapeutic potential. A proportion of these plant-derived compounds or phytochemicals were shown to be highly competent anticancer agents besides being effective against many other diseases. Representative compounds of different classes of phytochemicals are in clinical use against cancer. In this chapter, we discuss the anticancer potential of two compounds: quercetin, a flavonoid and tryptanthrin, an indoloquinazoline alkaloid, and the mechanisms behind their cytotoxic effects on cancers of different origin. The chapter also gives a brief mention of their properties that make them effective against cancer.
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