Achillin Increases Chemosensitivity to Paclitaxel, Overcoming Resistance and Enhancing Apoptosis in Human Hepatocellular Carcinoma Cell Line Resistant to Paclitaxel (Hep3B/PTX)

Pharmaceutics. 2019 Oct 4;11(10):512. doi: 10.3390/pharmaceutics11100512.

Jessica Nayelli Sanchez-Carranza ¹ ², Leticia González-Maya ³, Rodrigo Said Razo-Hernández ⁴, Enrique Salas-Vidal ⁵, Ninfa Yaret Nolasco-Quintana ⁶ ⁷, Aldo F Clemente-Soto ⁸ ⁹, Lucero García-Arizmendi ¹⁰, Mariana Sánchez-Ramos ¹¹, Silvia Marquina ¹², Laura Alvarez ¹³

Affiliations

1 Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa C.P. 62209, Cuernavaca, Mexico. jessica.sanchez@uaem.mx.
2 Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa C.P. 62209, Cuernavaca, Mexico. jessica.sanchez@uaem.mx.
3 Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa C.P. 62209, Cuernavaca, Mexico. letymaya@uaem.mx.
4 Centro de Investigación en Dinámica Celular-IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Chamilpa, Cuernavaca 62209, Morelos, Mexico. rodrigo.razo@uaem.mx.
5 Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca C.P. 62209, Morelos, Mexico. esalas@ibt.unam.mx.
6 Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa C.P. 62209, Cuernavaca, Mexico. nqny11@hotmail.com.
7 Centro de Investigación en Dinámica Celular-IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Chamilpa, Cuernavaca 62209, Morelos, Mexico. nqny11@hotmail.com.
8 Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa C.P. 62209, Cuernavaca, Mexico. aldoclemente13@hotmail.com.
9 Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa. Av. de las Américas y Blvd. Universitarios S/N, Culiacán 80010, Sinaloa, Mexico. aldoclemente13@hotmail.com.
10 Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa C.P. 62209, Cuernavaca, Mexico. lucero.gariz@gmail.com.
11 Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa C.P. 62209, Cuernavaca, Mexico. marianasan_06@hotmail.com.
12 Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa C.P. 62209, Cuernavaca, Mexico. smarquina@uaem.mx.
13 Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa C.P. 62209, Cuernavaca, Mexico. lalvarez@uaem.mx.

PMID: 31590262 DOI: 10.3390/pharmaceutics11100512

Abstract

Multidrug resistance (MDR) has become a major obstacle in the treatment of Cancer, and is associated with mechanisms such as increased drug outflow, reduction of Apoptosis, and/or altered drug metabolism. These problems can be mitigated by the coadministration of agents known as chemosensitizers, as they can reverse resistance to Anticancer drugs and eventually resensitize Cancer cells. We explore the chemosensitizing effect of Achillin, a guaianolide-type sesquiterpene lactone isolated from the Mexican medicinal plant Artemisia ludovisiana, to reverse MDR in Hep3B/PTX cells of hepatocellular carcinoma, which present resistance to paclitaxel (PTX). Achillin showed an important effect as chemosensitizer; indeed, the cytotoxic effect of PTX (25 nM) was enhanced, and the induction of G2/M phase cell cycle arrest and Apoptosis were potentiated when combining with Achillin (100 μM). In addition, we observed that Achillin decreases P-gp levels and increases the intracellular retention of doxorubicin in Hep3B/PTX cells; in addition, homology structural modeling and molecular docking calculations predicted that Achillin interacts in two regions (M-site and R-site) of transporter drug efflux P-glycoprotein (P-gp). Our results suggest that the chemosensitizer effect demonstrated for Achillin could be associated with P-gp modulation. This work also provides useful information for the development of new therapeutic agents from guaianolide-type sesquiterpene lactones like Achillin.

Keywords

Achillin; Chemosensitization; P-glycoprotein; hepatocellular carcinoma; multidrug resistance; paclitaxel.

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HY-121196

Achillin

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