Quantitative evaluation of ABC transporter-mediated drug resistance based on the determination of the anticancer activity of camptothecin against breast cancer stem cells using TIRF

Arumugam, Parthasarathy,Song, Joon Myong Oxford University Press 2016 Integrative biology Vol.8 No.6

<P>Elevated expression of drug efflux pumps such as multidrug resistant protein-1 (MDR1/ABCB1) and multidrug resistance associated protein-1 (MRP1/ABCC1) in cancer stem cells (CSCs) among a bulky tumor cell population was attributed to drug resistance. For the first time, we have quantitatively evaluated the cytotoxic profile of camptothecin (CPT) against the CSC. In the present study, a Qdot based total internal reflection fluorescence (TIRF) detection system effectively interpreted that drug resistance to CPT was reduced in the CSC under ABCB1 inhibited conditions. This study revealed that quantitative finding of the EC50 value for apoptosis and necrosis in correlation with the ABC inhibitor and CSC population using TIRF could provide more details of the anti-cancer efficacy of chemotherapeutic agents.</P>

Quantum-dot nanoprobes and AOTF based cross talk eliminated six color imaging of biomolecules in cellular system

Park, Solji,Arumugam, Parthasarathy,Purushothaman, Baskaran,Kim, Sung-Yon,Min, Dal-Hee,Jeon, Noo Li,Song, Joon Myong Elsevier 2017 Analytica chimica acta Vol.985 No.-

<P><B>Abstract</B></P> <P>Primary cell cultures mimic the physiology and genetic makeup of in-vivo tissue of origin, nonetheless, a complication in the derivation and propagation of primary cell culture limits its use in biological research. However, in-vitro models using primary cells might be a complement model to mimic in vivo response. But, conventional techniques such as western blot and PCR employed to study the expression and activation of proteins requires a large number of cells, hence repeated establishment and maintenance of primary culture are unavoidable. Quantum dot (Q-dot) and acousto-optic tunable filters (AOTF) based multiplex imaging system is a viable alternative choice to evaluate multiple signaling molecules by using a small number of cells. Q-dots have broad excitation and narrow emission spectra, which allows to simultaneously excite multiple Q-dots by using single excitation wavelength. The use of AOTF in the fluorescence detection system enables to scan the fluorescence emission intensity of a Q-dot at their central wavelength, this phenomenon effectively avoids spectral overlap among the neighboring Q-dots. When Q-dots are conjugated with antibodies it acts as effective sensing probes. To validate this, the expression pattern of p-JNK-1, p-GSK3β, p-IRS1ser, p-IRS1tyr, p-FOXO1, and PPAR-γ, involved in the insulin resistance were concurrently monitored in adipocyte and HepG2 co-cell culture model. The observed results clearly indicate that PPAR-γ is the critical component in the development of insulin resistance. Moreover, the results proved that developed Q-dot based AOTF imaging methodology is a sensible choice to concurrently monitor multiple signaling molecules with limited cell population.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Quantum dot (Q-dot) and acousto-optic tunable filters (AOTF) based six-colour imaging. </LI> <LI> Expression of PPAR-γ in adipocyte regulates insulin resistance in hepatic (HepG2) cells. </LI> <LI> Aspirin improved insulin sensitivity in adipocytes and HepG2 co-cell culture. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Design, synthesis, and biological evaluation of novel catecholopyrimidine based PDE4 inhibitor for the treatment of atopic dermatitis

Purushothaman, Baskaran,Arumugam, Parthasarathy,Kulsi, Goutam,Song, Joon Myong Elsevier 2018 European journal of medicinal chemistry Vol.145 No.-

<P><B>Abstract</B></P> <P>Selective inhibition of phosphodiesterase (PDE) 4B favorably suppresses the synthesis of inflammatory cytokines and subsequently arrest the development of atopic dermatitis via modulating the intracellular cAMP levels. Considering the side effects of corticosteroids, selective PDE4 inhibition could constitute an effective alternative therapy for the treatment of atopic dermatitis (AD). In this study, a series of novel catechol based compounds bearing pyrimidine as the core have been synthesized and screened for the PDE4 inhibitory properties. The PDE4 selectivity of the active compounds over other PDEs has been investigated. Compound <B>23</B> bearing pyrimidine core functionalized with catechol, pyridine and trifluoromethyl groups can effectively inhibit the PDE4B with IC<SUB>50</SUB> value in nanomolar range (IC<SUB>50</SUB> = 15 ± 0.4 nM). Compound <B>23</B> exhibited seven fold higher selectivity towards PDE4B over PDE4D. Molecular Docking study confirmed its stronger affinity towards catalytic domain of PDE4B. <I>In-vivo</I> analysis confirmed that compound <B>23</B> effectively alleviated the symptoms of atopic dermatitis in DNCB–treated Balb/c mice by suppressing the synthesis of inflammatory mediators such as TNF-α, and Ig-E. Taken together, this study suggested that compound <B>23</B> could be an effective PDE4 inhibitor for the potential treatment of AD.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A series of novel catecholopyrimidine derivatives was synthesized. </LI> <LI> All compounds showed excellent PDE4B inhibition activity. </LI> <LI> The docking study was performed for the active compound <B>23</B>. </LI> <LI> In-vivo atopic animal study was performed for compound <B>23</B>. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Novel ruthenium(II) triazine complex [Ru(bdpta)(tpy)]²⁺ co-targeting drug resistant GRP78 and subcellular organelles in cancer stem cells

Purushothaman, Baskaran,Arumugam, Parthasarathy,Ju, Hee,Kulsi, Goutam,Samson, Annie Agnes Suganya,Song, Joon Myong Elsevier 2018 European journal of medicinal chemistry Vol.156 No.-

<P><B>Abstract</B></P> <P>Ruthenium(II/III) metal complexes have been widely recognized as the alternative chemotherapeutic agents to overcome the drug resistance and tumor recurrence associated with platinum derivatives. In this work, a novel ruthenium(II) triazine complex namely, <B>1</B> ([Ru(bdpta)(tpy)]<SUP>2+</SUP>) was synthesized and spectroscopically characterized. Drug resistant cancer stem cells (CSCs) were used to evaluate the cytotoxicity of Ru(II) complex <B>1</B>. The complex <B>1</B> showed a greater cytotoxic potential with IC<SUB>50</SUB> values lower than that of cisplatin. The intracellular localization assay confirmed that the complex <B>1</B> was effectively distributed into mitochondria as well as endoplasmic reticulum (ER), and executed a ROS-mediated calcium and Bax/Bak dependent intrinsic apoptosis. Interestingly, direct interaction between complex <B>1</B> and glucose regulated protein 78 (GRP78), a protein associated with drug resistance caused the ROS-mediated ubiquitination of GRP78. Notably, western blot and confocal microscopy analysis confirmed that complex <B>1</B> significantly reduced the protein levels of GRP78. Dose-dependent <I>in vivo</I> antitumor efficacy against CD133+HCT-116 CSCs derived tumor xenograft further validated that complex <B>1</B> could be an effective chemotherapeutic agent.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The novel ruthenium(II) triazine complex <B>1</B> was synthesized and characterized. </LI> <LI> The cytotoxicity study of ruthenium(II) triazine complex <B>1</B> was evaluated against cisplatin in cancer stem cells (CSCs). </LI> <LI> Complex <B>1</B> was mainly accumulated in mitochondria and endoplasmic reticulum (ER). </LI> <LI> Direct interaction between complex <B>1</B> and glucose regulated protein 78 (GRP78), caused ROS mediated ubiquitination of GRP78. </LI> <LI> Dose-dependent <I>in vivo</I> antitumor efficacy of complex <B>1</B> was investigated. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Synthesis, Characterization, and Antihyperglycemic Activity of Novel Oxazolidine Derivatives

Theivendren Panneer Selvam,Palanirajan Vijayaraj Kumar,Parthasarathi Ramu,Arumugam Siva Kumar 대한약학회 2011 Archives of Pharmacal Research Vol.34 No.6

A number of compounds have been prepared in order to improve pharmacological roles of antihyperglycemic activity. In the present paper, a series of 3-benzyl-2-(4'-substituted phenyl)-4(5H)-(4''-nitrophenyl amino)-1,3-oxazolidines (6a-e) were tested against hyperglycemia. Their antihyperglycemic activity was evaluated by streptozotocin (STZ) and sucrose-loaded (SLM) models. Compounds 6a, b, c, d, and e displayed significant reductions in blood glucose in the streptozotocin and sucrose loaded rat models. The purity of the synthesized compounds was characterized by means of IR, 1H-NMR, mass spectral and elemental analysis.