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7-Hydroxy-4-methoxy-5-methylcoumarin: A Further 5-Metylcoumrin from Toona ciliata(Meliaceae)
Rasheduzzaman Chowdhury,Aliza Ahmed,Md. Zakiur Rahman 한국생약학회 2004 Natural Product Sciences Vol.10 No.3
A 5-C-methylcoumarin was isolated from the petroleum ether extract of Toona ciliata stem bark. Its structure was established as 7-Hydroxy-4-methoxy-5-methylcoumarin on the basis of spectral data, including 2D NMR.
Rasheduzzaman, Mohammad,Jeong, Jae-Kyo,Park, Sang-Youel Elsevier 2018 Life sciences Vol.208 No.-
<P><B>Abstract</B></P> <P><B>Aims</B></P> <P>TRAIL is a promising anticancer agent that has the potential to sensitize a wide variety of cancer or transformed cells by inducing apoptosis. However, resistance to TRAIL is a growing concern. Current manuscript aimed to employ combination treatment to investigate resveratrol induced TRAIL sensitization in NSCLC.</P> <P><B>Method</B></P> <P>A549 and HCC-15 cells were used in an experimental design. Cell viability was determined by morphological image, crystal violet staining and MTT assay. Apoptosis was evaluated by LDH assay, Annexin V and DAPI staining. Autophagy and apoptosis indicator protein were examined by western blotting. TEM and puncta assay was carried out to evaluate the autophagy. MTP and ROS activity was evaluated by JC-1 and H<SUB>2</SUB>DCFDA staining.</P> <P><B>Findings</B></P> <P>Resveratrol is a polyphenolic compound capable of activation of tumor suppressor p53 and its pro-apoptotic modulator PUMA. Herein, we showed the p53-independent apoptosis by decrease the expression of phosphorylated Akt-mediated suppression of NF-κB that is also substantiated with the downregulation of anti-apoptotic factors Bcl-2 and Bcl-xl in NSCLC, resulting in an attenuation of TRAIL resistance in combined treatment. Furthermore, apoptosis was induced in TRAIL-resistant lung cancer cells with a co-treatment of resveratrol and TRAIL assessed by the loss of MMP, ROS generations which resulting the translocation of cytochrome <I>c</I> from the mitochondria into the cytosol due to mitochondrial dysfunction. Moreover, autophagy flux was not affected by resveratrol-induced TRAIL-mediated apoptosis in NSCLC.</P> <P><B>Significance</B></P> <P>Overall, targeting the NF-κB (p65) pathway via resveratrol attenuates TRAIL resistance and induces TRAIL-mediated apoptosis which could be the effective TRAIL-based cancer therapy regimen.</P>
Evaluation of Clofazimine as a Potential Substrate and Inhibition on P-glycoprotein in Vitro
( Rasheduzzaman Jony ),( Nguyen Ky Phat ),( Ho Jung Shin ),( Nguyen Phuoc Long ),( Yong-soon Cho ),( Jae-gook Shin ) 대한결핵 및 호흡기학회 2020 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.128 No.-
Background Clofazimine (CFZ) is a second-line anti-tuberculosis (anti-TB) drug. Approximately 35% to 50% of CFZ has recovered in faeces, which represents the unabsorbed or bile excretion of CFZ. Except for being a P-glycoprotein (P-gp) substrate, it is limited to know about the efflux transporters' involvement with CFZ absorption and bile excretion. Furthermore, the efficacy and safety of CFZ in a multiple drug-regimen remain to be studied. We investigated to explore the interactions of CFZ with efflux transporters and potential transporter-mediated drug-drug interaction (DDI). Methods Intracellular accumulation assay was conducted using porcine kidney cells (LLC-PK1) that stably overexpressed human P-gp transporter. The transport assay was carried out in the absence or presence of P-gp inhibitor (Verapamil; VPL) in a concentration gradient manner, and the intracellular accumulated concentration was then quantified. The inhibitory constant (Ki) of verapamil was estimated via the Lineweaver-Burke plot. Furthermore, DDI index was calculated following the guideline by the US Food and Drug Administration. A Physiologically Based Pharmacokinetic (PBPK) Model to predict the DDI risk in terms of CFZ and P-gp interaction to elucidate the underlying mechanism. Results Intracellular accumulation data indicated a strong P-gp mediated DDI between the P-gp substrate CFZ and the inhibitor VPL with the 7-gradient of up to 200μM of concentration. The estimated Ki of the verapamil was found to be 67.7μM. Furthermore, the DDI index for the VPL on CFZ were 0.01 for liver and 31.2 for intestine, suggesting a potential clinical DDI interaction on GI-P-gp. We conducted the extrapolation of in vitro data to in vivo using PBPK modelling. The basic DDI model of CFZ and VPL was validated with curated clinical data. Conclusion Collectively, our findings suggested that P-gp efflux transporter involves in the CFZ transport and P-gp inhibitor appears to have a potential DDI with CFZ.
Rasheduzzaman, Mohammad,Park, Sang-Youel Elsevier 2018 Experimental cell research Vol.368 No.1
<P><B>Abstract</B></P> <P>Angiotensin II type 1 receptor blockers (ARBs) are widely used as antihypertensive drugs. Candesartan is an ARB that has also been known for its anticancer effects but the exact molecular mechanism is remaining elusive. In this research, we showed for the first time that candesartan treatment significantly sensitized human lung adenocarcinoma cells to Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by targeting TRAIL-DR5. TRAIL selectively kills cancer cells by binding to death receptors on the cell membrane, beyond the levels causing minimal toxicity in normal cells. However, some non-small-cell lung carcinoma (NSCLC) patients are resistant to TRAIL treatment in clinical trials due to inactivation of the death receptors during cytoprotective autophagy. The molecular mechanisms underlying candesartan-induced TRAIL-mediated apoptosis involved the downstream of AMPK phosphorylation resulting inhibition of autophagy flux, recruitment of death receptor 5 (DR5) and activation of apoptotic caspase cascade. Candesartan treatment also inhibits the expression of anti-apoptotic protein c-FLIP. Furthermore, blocking DR5 signaling using DR5 siRNA negatively regulated the apoptotic pathway and also induced autophagy flux, demonstrating the cytoprotective role of autophagy responsible for treatment resistance. This suggests that candesartan can be used to sensitize tumors to TRAIL treatment and may represent a useful strategy for human adenocarcinoma patients to overcome TRAIL resistance. Candesartan in combination with TRAIL also could be a novel therapeutic treatment for patients presenting both conditions of hypertension and lung cancer.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Candesartan sensitizes lung adenocarcinoma to TRAIL via targeting TRAIL-DR5. </LI> <LI> Autophagy inhibition by candesartan recruit DR5, induces TRAIL mediated caspase cascade. </LI> <LI> Candesartan down regulate cFLIP, attenuates TRAIL resistance to lung adenocarcinoma. </LI> <LI> Candesartan synergistic to TRAIL for patients presenting both hypertension and cancer. </LI> </UL> </P>
Rasheduzzaman, Mohammad,Moon, Ji-Hong,Lee, Ju-Hee,Nazim, Uddin Md,Park, Sang-Youel Pergamon 2018 The international journal of biochemistry & cell b Vol.102 No.-
<P><B>Abstract</B></P> <P>Telmisartan broadly used for the treatment of hypertension that is also known for its anticancer properties. TRAIL has the potential to kill tumor cells with minimal toxicity in normal cells by binding to death receptors, DR4 and DR5. Unfortunately, these TRAIL-death receptors have failed as most human cancers are resistant to TRAIL-mediated apoptosis. In this study, we evaluated telmisartan as a novel TRAIL-DR5-targeting agent with the aim of rendering TRAIL-based cancer therapies more active. Herein, we demonstrated that telmisartan could sensitize TRAIL and enhance NSCLC tumor cell death. The molecular mechanism includes the blocking of AMPK phosphorylation causes inhibition of autophagy flux by telmisartan resulting in ROS generation leading to death receptor (DR5) upregulation and subsequent activation of the caspase cascade by TRAIL treatment. Furthermore, using chloroquine and siATG5 significantly enhances ROS production and application of the ROS scavenger N-acetyl-cysteine (NAC) rescues the cells undergoing apoptosis by abrogating the expression of DR5 and finally the caspase cascade. Additionally, NAC treatment also maintains autophagy flux and makes the cells unresponsive to TRAIL. In summary, telmisartan in combination with TRAIL exhibits enhanced cytotoxic capacity toward lung cancer cells, thereby providing the potential for effective and novel therapeutic approaches to treat lung cancer.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Telmisartan upregulates DR5 to functionalize TRAIL in lung adenocarcinoma. </LI> <LI> Autophagy inhibition by telmisartan confers ROS generations to uphold DR5 and arouses TRAIL- mediated apoptosis. </LI> <LI> Telmisartan induced TRAIL sensitization is independent of PPARγ. </LI> <LI> Telmisartan effective to TRAIL, thereby providing the synergistic potential for the patient presenting both conditions of hypertension and cancer. </LI> </UL> </P>