<?xml version="1.0" encoding="ISO-8859-1"?><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
<front>
<journal-meta>
<journal-id>0535-5133</journal-id>
<journal-title><![CDATA[Investigación Clínica]]></journal-title>
<abbrev-journal-title><![CDATA[Invest. clín]]></abbrev-journal-title>
<issn>0535-5133</issn>
<publisher>
<publisher-name><![CDATA[Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia]]></publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id>S0535-51332022000300243</article-id>
<article-id pub-id-type="doi">10.54817/ic.v63n3a04</article-id>
<title-group>
<article-title xml:lang="en"><![CDATA[Effect of tetrahydroquinoline derivatives on the intracellular Ca2+ homeostasis in breast cancer cells (MCF-7) and its relationship with apoptosis.]]></article-title>
<article-title xml:lang="es"><![CDATA[Efecto de derivados de tetrahidroquinolinas sobre la homeostasis del Ca2+ intracelular en células de cáncer de mama (MCF-7) y su relación con la apoptosis.]]></article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Maksoud]]></surname>
<given-names><![CDATA[Semer]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Mayora]]></surname>
<given-names><![CDATA[Adriana]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Colman]]></surname>
<given-names><![CDATA[Laura]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Sojo]]></surname>
<given-names><![CDATA[Felipe]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
<xref ref-type="aff" rid="Aaf"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Pimentel]]></surname>
<given-names><![CDATA[Adriana A.]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Kouznetsov]]></surname>
<given-names><![CDATA[Vladimir V.]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Merchán-Arenas]]></surname>
<given-names><![CDATA[Diego R.]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Romero]]></surname>
<given-names><![CDATA[Ángel H.]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Arvelo]]></surname>
<given-names><![CDATA[Francisco]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
<xref ref-type="aff" rid="Aaf"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[De Sanctis]]></surname>
<given-names><![CDATA[Juan Bautista]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Benaim]]></surname>
<given-names><![CDATA[Gustavo]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
<xref ref-type="aff" rid="A a"/>
<xref ref-type="aff" rid="A11"/>
</contrib>
</contrib-group>
<aff id="Af1">
<institution><![CDATA[,Massachusetts General Hospital Department of Neurology and Experimental Therapeutics and Molecular Imaging Laboratory ]]></institution>
<addr-line><![CDATA[ MA]]></addr-line>
<country>USA</country>
</aff>
<aff id="Af2">
<institution><![CDATA[,Universidad Central de Venezuela Facultad de Medicina Instituto de Medicina Experimental]]></institution>
<addr-line><![CDATA[Caracas ]]></addr-line>
<country>Venezuela</country>
</aff>
<aff id="Af3">
<institution><![CDATA[,Instituto Pasteur  ]]></institution>
<addr-line><![CDATA[Montevideo ]]></addr-line>
<country>Uruguay</country>
</aff>
<aff id="Af4">
<institution><![CDATA[,Fundación Instituto de Estudios Avanzados (IDEA) Centro de Biociencias ]]></institution>
<addr-line><![CDATA[Caracas ]]></addr-line>
<country>Venezuela</country>
</aff>
<aff id="Af5">
<institution><![CDATA[,Universidad Central de Venezuela Instituto de Biología Experimental Laboratorio de Cultivo de Tejidos y Biología de Tumores]]></institution>
<addr-line><![CDATA[Caracas ]]></addr-line>
<country>Venezuela</country>
</aff>
<aff id="Af6">
<institution><![CDATA[,Universidad Central de Venezuela Facultad de Farmacia ]]></institution>
<addr-line><![CDATA[Caracas ]]></addr-line>
<country>Venezuela</country>
</aff>
<aff id="Af7">
<institution><![CDATA[,Universidad Industrial de Santander Parque Tecnológico Guatiguara Laboratorio de Qui&#769;mica Orga&#769;nica y Biomolecular (CMN)]]></institution>
<addr-line><![CDATA[Piedecuesta ]]></addr-line>
<country>Colombia</country>
</aff>
<aff id="Af8">
<institution><![CDATA[,Universidad Central de Venezuela Facultad de Farmacia Cátedra de Química General]]></institution>
<addr-line><![CDATA[Caracas ]]></addr-line>
<country>Venezuela</country>
</aff>
<aff id="Af9">
<institution><![CDATA[,Palacky Unversity Institute of Molecular and Translational Medicine ]]></institution>
<addr-line><![CDATA[Olomouc ]]></addr-line>
<country>Czech Republic</country>
</aff>
<aff id="A10">
<institution><![CDATA[,Instituto de Estudios Avanzados (IDEA) Laboratorio de Señalización Celular y Bioquímica de Parásitos ]]></institution>
<addr-line><![CDATA[Caracas ]]></addr-line>
<country>Venezuela</country>
</aff>
<aff id="A11">
<institution><![CDATA[,Universidad Central de Venezuela Instituto de Biología Experimental ]]></institution>
<addr-line><![CDATA[Caracas ]]></addr-line>
<country>Venezuela</country>
</aff>
<pub-date pub-type="pub">
<day>00</day>
<month>09</month>
<year>2022</year>
</pub-date>
<pub-date pub-type="epub">
<day>00</day>
<month>09</month>
<year>2022</year>
</pub-date>
<volume>63</volume>
<numero>3</numero>
<fpage>243</fpage>
<lpage>261</lpage>
<copyright-statement/>
<copyright-year/>
<self-uri xlink:href="http://ve.scielo.org/scielo.php?script=sci_arttext&amp;pid=S0535-51332022000300243&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://ve.scielo.org/scielo.php?script=sci_abstract&amp;pid=S0535-51332022000300243&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://ve.scielo.org/scielo.php?script=sci_pdf&amp;pid=S0535-51332022000300243&amp;lng=en&amp;nrm=iso"></self-uri><abstract abstract-type="short" xml:lang="en"><p><![CDATA[Abstract Tetrahydroquinoline derivatives are interesting structures exhibiting a wide range of biological activities, including antitumor effects. In this investigation, the effect of the synthesized tetrahydroquinolines JS-56 and JS-92 on apoptosis, intracellular Ca2+ concentration ([Ca2+]i), and the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity was determined on MCF-7 breast cancer cells. Colorimetric assays were used to assess MCF-7 cells viability and SERCA activity. Fura-2 and rhodamine 123 were used to measure the intracellular Ca2+ concentration and the mitochondrial electrochemical potential, respec tively. TUNEL assay was used to analyze DNA fragmentation, while caspase activity and NF-&#954;B-dependent gene expression were assessed by luminescence. In silico models were used for molecular docking analysis. These compounds increase intracellular Ca2+ concentration; the main contribution is the Ca2+ entry from the extracellular milieu. Both JS-56 and JS-92 inhibit the activity of SERCA and dissipate the mitochondrial electrochemical potential through processes dependent and independent of the Ca2+ uptake by this organelle. Furthermore, JS-56 and JS-92 generate cytotoxicity in MCF-7 cells. The effect of JS-92 is higher than JS-56. Both compounds activate caspases 7 and 9, cause DNA fragmentation, and potentiate the effect of phorbol 12-myristate-13-acetate on NF-&#954;B-dependent gene expression. Molecular docking analysis suggests that both compounds have a high interaction for SERCA, similar to thapsigargin. Both tetrahydroquinoline derivatives induced cell death through a combination of apoptotic events, increase [Ca2+]i, and inhibit SERCA activity by direct interaction.]]></p></abstract>
<abstract abstract-type="short" xml:lang="es"><p><![CDATA[Resumen Los derivados de tetrahidroquinolina son estructuras interesantes que exhiben una amplia gama de actividades biológicas, incluyendo efectos antitumorales. Se determinó el efecto de las tetrahidroquinolinas sintetizadas JS-56 y JS-92 sobre la apoptosis, concentración intracelular de Ca2+ ([Ca2+]i) y la actividad Ca2+-ATPasa del retículo sarco(endo)plásmico (SERCA) en células de cáncer de mama MCF-7. Se usaron ensayos colorimétricos para evaluar la viabilidad de las células MCF-7 y la actividad SERCA. Se emplearon Fura-2 y rodamina 123 para medir la concentración de Ca2+ intracelular y el potencial electroquímico mitocondrial, respectivamente. El ensayo TUNEL se utilizó para analizar la fragmentación del ADN, mientras que la actividad de caspasas y la expresión génica dependiente de NF-&#954;B se evaluaron mediante luminiscencia. Modelos in silico permitieron el análisis del acoplamiento molecular. Estos compuestos aumentan la concentración de Ca2+ intracelular; la principal contribución es la entrada de Ca2+ desde el medio extracelular. Tanto JS-56 como JS-92 inhiben la actividad de SERCA y disipan el potencial electroquímico mitocondrial a través de procesos dependientes e independientes de la captación de Ca2+ por este orgánulo. Además, JS-56 y JS-92 generan citotoxicidad en células MCF-7. El efecto de JS-92 es mayor que JS-56. Ambos compuestos activan las caspasas 7 y 9, provocan la fragmentación del ADN y potencian el efecto del 12-miristato-13-acetato de forbol en la expresión génica dependiente de NF-&#954;B. El análisis de acoplamiento molecular sugiere que ambos compuestos tienen una alta interacción con SERCA, similar a la tapsigargina. Ambos derivados de tetrahidroquinolina indujeron la muerte celular a través de una combinación de eventos apoptóticos, aumento de [Ca2+]i e inhibición de la actividad SERCA por interacción directa.]]></p></abstract>
<kwd-group>
<kwd lng="en"><![CDATA[Ca2+]]></kwd>
<kwd lng="en"><![CDATA[apoptosis]]></kwd>
<kwd lng="en"><![CDATA[tetrahydroquinolines]]></kwd>
<kwd lng="en"><![CDATA[mitocondria]]></kwd>
<kwd lng="en"><![CDATA[SERCA]]></kwd>
<kwd lng="en"><![CDATA[NF-&#954;B]]></kwd>
<kwd lng="es"><![CDATA[Ca2+]]></kwd>
<kwd lng="es"><![CDATA[apoptosis]]></kwd>
<kwd lng="es"><![CDATA[tetrahidroquinolinas]]></kwd>
<kwd lng="es"><![CDATA[Mitocondria]]></kwd>
<kwd lng="es"><![CDATA[SERCA]]></kwd>
<kwd lng="es"><![CDATA[NF-&#954;B]]></kwd>
</kwd-group>
</article-meta>
</front><back>
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