Cancer Research Initiative Foundation

Subang Jaya, Malaysia

Cancer Research Initiative Foundation

Subang Jaya, Malaysia
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Hasima N.,University of Malaya | Aun L.I.L.,University of Malaya | Azmi M.N.,University of Malaya | Aziz A.N.,University of Malaysia, Terengganu | And 3 more authors.
Phytomedicine | Year: 2010

Medicinal plants containing active natural compounds have been used as an alternative treatment for cancer patients in many parts of the world especially in Asia (Itharat et al. 2004). In this report, we describe the cytotoxic and apoptotic properties of 1'S-1'-acetoxyeugenol acetate (AEA), an analogue of 1'S-1'-acetoxychavicol acetate (ACA), isolated from the Malaysian ethno-medicinal plant Alpinia conchigera Griff (Zingiberaceae) on human breast cancer cells. Data from MTT cell viability assays indicated that AEA induced both time- and dose-dependant cytotoxicity with an IC50 value of 14.0μM within 36h of treatment on MCF-7 cells, but not in HMEC normal control cells. Both annexin V-FITC/PI flow cytometric analysis and DNA fragmentation assays confirmed that AEA induced cell death via apoptosis. AEA was also found to induce cell cycle arrest in MCF-7 cells at the G0/G1 phase with no adverse cell cycle arrest effects on HMEC normal control cells. It was concluded that AEA isolated from the Malaysian tropical ginger represents a potential chemotherapeutic agent against human breast cancer cells with higher cytotoxicity potency than its analogue, ACA. © 2010 Elsevier GmbH.


Tailor N.K.,Jaypee University of Information Technology | Boon H.L.,Cancer Research Initiative Foundation | Sharma M.,Jaypee University of Information Technology
European Journal of Medicinal Chemistry | Year: 2013

The antitumor pentacyclic triterpenoids, Lantadene A (1) and B (2) were isolated from the leaves of weed Lantana camara L. (Verbenaceae) and were structurally transformed to bioactive intermediates 3-6. The Claisen-Schmidt reaction of 22β-hydroxy-3-oxoolean-12-en-28-oic acid (5) with requisite aldehydes afforded 2-arylidene-22β-hydroxy-3-oxoolean-12-en-28-oic acids (7-16). The compounds were evaluated for their in-vitro anticancer activity by National Cancer Institute (NCI), USA and some of these compounds showed marked cytotoxicity in micromolar range. The mean graph midpoint (MG-MID) value of compound 3 (MG-MID -5.69) was higher than standard drug cisplatin (MG-MID -5.66) while comparable in case of compound 12 (MG-MID -5.52). The NCI's COMPARE molecular mechanistic analysis showed that these compounds were in significant correlations with activity patterns of mechanistic set of compounds (PCC ≥ 0.60). © 2013 Elsevier Inc. All rights reserved.


Monika,Jaypee University of Information Technology | Sharma A.,Jaypee University of Information Technology | Suthar S.K.,Jaypee University of Information Technology | Aggarwal V.,Jaypee University of Information Technology | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22β-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar activity against TNF-α induced activation of NF-κB and exhibited inhibition of IKKβ in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC50 of 0.98 μM. The Western blot analysis further showed that the suppression of NF-κB activity by the lead analog 11 was due to the inhibition of IκBα degradation, a natural inhibitor of NF-κB. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKKβ. © 2014 Elsevier Ltd. All rights reserved.


Tailor N.K.,Jaypee University of Information Technology | Jaiswal V.,Jaypee University of Information Technology | Lan S.S.,Cancer Research Initiative Foundation | Lee H.B.,Cancer Research Initiative Foundation | Sharma M.,Jaypee University of Information Technology
Anti-Cancer Agents in Medicinal Chemistry | Year: 2013

The ring A and D substituted analogs of pentacyclic triterpenoid Lantadene A (1) and B (2) were synthesized and evaluated for in vitro anticancer activity against four human cancer cell lines (HL-60, MCF-7, A549 and HCT-116). Analogs 3, 4, 7 and 8 showed enhanced inhibitory activity as compared with 1 and 2. These analogs were found more active than standard drug cisplatin with selective toxicity towards cancer cells and were inactive against normal cells (VERO). Furthermore, the mechanistic studies to investigate the effects of the new compounds on Akt protein in lung cancer cell line A549 and the NF-κB signalling pathway suggested that the compounds may exert their inhibitory activity on cancer cells through inhibition of both Akt and NF-κB activation. The docking studies of most potent analog (7) with 3D crystal structure of the nuclear factor kappa-B (NF-κB) P50 homodimer (PDB ID: 1NFK) revealed that carbonyl group of ester side chain and C-28 carboxylic acid groups were mainly involved in hydrogen bonding interaction. The oleanane frameworks was involved in strong hydrophobic interaction with amino acid phenylalanine and structure of lead compound have the potential to be developed as potent NF-κB inhibitor and anticancer agent. © 2013 Bentham Science Publishers.


Suthar S.K.,Jaypee University of Information Technology | Boon H.L.,Cancer Research Initiative Foundation | Sharma M.,Jaypee University of Information Technology
European Journal of Medicinal Chemistry | Year: 2014

The C-3, C-17 and C-22 congeners of pentacyclic triterpenoids reduced lantadene A (3), B (4) and 22β-hydroxyoleanolic acid (5) were synthesized and were tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead congeners 12 and 13 showed IC50 of 0.56 and 0.42 μmol, respectively against TNF-α induced activation of NF-κB. The congeners 12 and 13 exhibited inhibition of IKKβ in a single-digit micromolar dose and at the same time, 12 and 13 showed marked cytotoxicity against A549 lung cancer cells with IC50 of 0.12 and 0.08 μmol, respectively. The lead ester congeners were stable in the acidic pH, while hydrolyzed readily in the human blood plasma to release the active parent moieties. © 2013 Elsevier B.V. All rights reserved.


Kumar S.S.,Jaypee University of Information Technology | Tailor N.,Jaypee University of Information Technology | Lee H.B.,Cancer Research Initiative Foundation | Sharma M.,Jaypee University of Information Technology
Medicinal Chemistry Research | Year: 2013

The aim of this study was to investigate the effect of pentacyclic triterpenoids-reduced Lantadenes A (3) and B (4) on the cytotoxicity, stimulation of apoptosis and regulation of transcription factors in HL-60 cells. The 3 and 4 are the minor compounds of weed Lantana camara L. (Verbenaceae) and were prepared semi-synthetically in single step by reducing Lantadenes A (1) and B (2) under microwave irradiation with yield of 98-99 %. The 3 and 4 demonstrated selective cytotoxicity against HL-60, MCF-7, HSC-2, and HCT-116 cancer cell lines (IC50 1.2-6.4 μM) and were found non-toxic toward normal cells (VERO) with IC50 >50). The compounds 3 and 4 (15 μM)-induced apoptosis by activation of caspase-3 and bax, along with significant decrease in expression of NF-kB (p-65) and bcl-2 in HL-60 cells. The compounds 3 and 4 at 15 μM significantly suppressed the production of nitrite, TNF-α, and iNOS gene expression in HL-60 cells. The results suggested that reduced Lantadenes A and B have the potential to be developed as anticancer agents. © 2012 Springer Science+Business Media New York.


Suthar S.K.,Jaypee University of Information Technology | Lee H.B.,Cancer Research Initiative Foundation | Sharma M.,Jaypee University of Information Technology
RSC Advances | Year: 2014

The ester conjugates of potent nuclear factor-kappa B (NF-κB) inhibitors with cyclooxygenase (COX) inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) present a novel approach towards cancer treatment. The ester prodrugs of pentacyclic triterpenoid 3β,22β-dihydroxy-olean-12-en-28- oic acid (4) with different NSAIDs were synthesized for the dual inhibition of NF-κB and COX-2. The results indicated that the lead compound 14 suppressed the tumor necrosis factor-alpha-induced (TNF-α-induced) activation of NF-κB by inhibiting the inhibitor of the nuclear factor-kappa B kinase (IKK) activation, the inhibitor of the nuclear factor-kappa B alpha (IκBα) degradation and at the same time, it down-regulated the NF-κB mediated protein expression of COX-2 and cyclin D1. Furthermore, compound 14 inhibited lung adenocarcinoma A549 cell proliferation in a dose dependent manner and was found to be 50 folds more active than cisplatin in terms of IC50. Compound 14 was also found to be stable in an acidic pH, while it hydrolyzed readily in human plasma to release the active promoieties. From the results it can be inferred that the lantadene-NSAID prodrugs are promising anticancer candidates against lung cancer with a dual inhibition capability against both NF-κB and COX-2. © the Partner Organisations 2014.


Tailor N.K.,Jaypee University of Information Technology | Lee H.B.,Cancer Research Initiative Foundation | Sharma M.,Jaypee University of Information Technology
Journal of Environmental Pathology, Toxicology and Oncology | Year: 2013

The C-2 arylidene analog (compound 3) of pentacyclic triterpenoid Lantadene A (compound 1) was synthesized and evaluated by the National Cancer Institute, USA, for in vitro cytotoxicity against a panel of melanoma cancer cell lines: LOX IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257 UACC-62 and B16F10. Compound 3 showed enhanced cytotoxicity compared with compound 1 and the standard drug cisplatin. At the same time, compound 3 showed selective toxicity toward cancer cells and was inactive (i.e., nontoxic) against normal cells (VERO). Compound 3 induced sub-G1 cell cycle arrest and apoptosis in B16F10 cells by down-regulating NF-k{cyrillic}B, c-jun, Bcl-2, and by activating caspase-3 and Bax expression. Compound 3 also demonstrated beneficial effects in a clinically relevant B16F10 allograft mice model, with significant reduction of tumor growth/tumor weight in vivo. Compound 3 improved the survival rate in comparison to the control group and the cisplatin group. At the same time, compound 3 had a better safety profile than cisplatin in terms of hematological parameters and liver enzyme levels. © 2013 Begell House, Inc.


Suthar S.K.,Jaypee University of Information Technology | Sharma N.,BAHRA University | Lee H.B.,Cancer Research Initiative Foundation | Nongalleima K.,Institute of Bioresources and Sustainable Development IBSD | Sharma M.,Jaypee University of Information Technology
Current Topics in Medicinal Chemistry | Year: 2014

The activation of transcription factors nuclear factor-kappa B (NF-κB) and cyclooxygenase-2 (COX-2) is critical in cancer; they act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of NF-κB and COX-2 present an opportunity for synergistic anticancer efficacy. The ester prodrugs of pentacyclic triterpenoids reduced lantadene A (3), B (4), and its congener 22β-hydroxyoleanonic acid (5) with various non steroidal anti-inflammatory drugs (NSAIDs) present a novel approach. The ester prodrugs of 3 and 4 with diclofenac showed promising dual inhibition of NF-κB and COX-2. The lead prodrugs 14 and 15 exhibited inhibition of inhibitor of nuclear factor-kappa B kinaseβ (IKKβ) in the single-digit micromolar range and at the same time, prodrugs 14 and 15 showed marked cytotoxicity against A549 lung cancer cell line with IC50s 0.15 and 0.42 μM, respectively. The prodrugs 14 and 15 exhibited stability in the acidic pH and were hydrolyzed readily in the human blood plasma to release the active parent moieties. Thus, we have synthesized novel hybrid compounds to target both NF-κB and COX-2 via a prodrug approach, leading to promising anticancer candidates. © 2014 Bentham Science Publishers.


PubMed | Jaypee University of Information Technology and Cancer Research Initiative Foundation
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2014

The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-B and IKK inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar activity against TNF- induced activation of NF-B and exhibited inhibition of IKK in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC50 of 0.98 M. The Western blot analysis further showed that the suppression of NF-B activity by the lead analog 11 was due to the inhibition of IB degradation, a natural inhibitor of NF-B. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKK.

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