Morpholine KECH-18D Restores Drug Sensitivity and Differentially Modulates Efflux Phenotypes in Cisplatin- and Paclitaxel-Resistant Cervical Cancer Cells

Aldo F. Clemente-Soto; Mireya Cisneros-Hernández; Nidia L. Duriez-Tizoc; Rodolfo Bernal-Reynaga; Mauricio Maldonado-Domínguez; Margarita Romero-Ávila; Jesús R. Parra-Unda; Francisco Delgado-Vargas; Marcela Martínez-Valenzuela

doi:10.31557/APJCB.2026.11.3.705

Authors

Aldo F. Clemente-Soto Faculty of Chemical Biological Sciences, Autonomous University of Sinaloa, 80030 Culiacán Rosales, Sinaloa, Mexico. https://orcid.org/0000-0002-3416-8915
Mireya Cisneros-Hernández Faculty of Biology, Autonomous University of Sinaloa, 80030 Culiacán Rosales, Sinaloa, Mexico. https://orcid.org/0009-0005-3698-6726
Nidia L. Duriez-Tizoc Faculty of Biology, Autonomous University of Sinaloa, 80030 Culiacán Rosales, Sinaloa, Mexico. https://orcid.org/0009-0001-2807-5931
Rodolfo Bernal-Reynaga Faculty of Chemical Biological Sciences, Autonomous University of Sinaloa, 80030 Culiacán Rosales, Sinaloa, Mexico. https://orcid.org/0000-0002-9501-4514
Mauricio Maldonado-Domínguez Faculty of Chemistry, National Autonomous University of Mexico, School Circuit S/N, Coyoacán, University City, CDMX, Mexico. https://orcid.org/0000-0002-4260-3032
Margarita Romero-Ávila Faculty of Chemistry, National Autonomous University of Mexico, School Circuit S/N, Coyoacán, University City, CDMX, Mexico. https://orcid.org/0000-0003-1736-3580
Jesús R. Parra-Unda Faculty of Chemical Biological Sciences, Autonomous University of Sinaloa, 80030 Culiacán Rosales, Sinaloa, Mexico. https://orcid.org/0000-0001-5291-6879
Francisco Delgado-Vargas Faculty of Chemical Biological Sciences, Autonomous University of Sinaloa, 80030 Culiacán Rosales, Sinaloa, Mexico. https://orcid.org/0000-0003-3369-5200
Marcela Martínez-Valenzuela Faculty of Chemical Biological Sciences, Autonomous University of Sinaloa, 80030 Culiacán Rosales, Sinaloa, Mexico. https://orcid.org/0000-0002-0855-0686

DOI:

https://doi.org/10.31557/APJCB.2026.11.3.705

Keywords:

Chemoresistance, Cisplatin-resistant cells, Paclitaxel-resistant cells, Morpholine KECH-18D, Drug efflux modulation

Abstract

Background: Chemoresistance represents a major obstacle in cancer therapy, often associated with enhanced drug efflux. This study aimed to generate and characterize cisplatin-resistance in C-33A cells (C-33A RCDDP), and included, for comparison, a previously established paclitaxel-resistant subline (C-33A RPTX) overexpressing transporters, such as ABCB1, ABCG4, and ABCC8. In addition, we assessed whether the morpholine KECH-18D could restore drug sensitivity by enhancing intracellular drug accumulation.

Materials and Methods: C-33A RCDDP cells were developed by stepwise cisplatin (CDDP) exposure. Cytotoxicity assays of nine morpholines were carried out to identify structural determinants of anticancer activity in the C-33A cell line. Combinatorial assays with morpholine KECH-18D and CDDP or paclitaxel (PTX) were performed to determine whether KECH-18D chemosensitizes and retains the drug in C-33A RCDDP and C-33A RPTX cells.

Results: C-33A RCDDP cells exhibited a 4.7-fold increase in CDDP resistance. C-33A RCDDP and C-33A RPTX cells both displayed cross-resistance patterns, but C-33A RTPX cells retained lower levels of the drug than C-33A RCDDP cells. Furthermore, KECH-18D maintained strong cytotoxicity against chemoresistant cell lines and enhanced the cytotoxicity of CDDP and PTX against them. Notably, KECH-18D increased drug accumulation in C-33A RCDDP cells in a time-dependent manner, but not in C-33A RPTX cells.

Conclusion: In summary, C-33A RCDDP and C-33A RPTX cells developed different levels, and possibly mechanisms, of resistance. Because the morpholine KECH-18D resulted highly cytotoxic in both parental and chemoresistant cells, enhanced drug retention in C-33A RCDDP cells and increased the toxicity of CDDP or PTX in chemoresistant cells, KECH-18D is a promising scaffold for overcoming multidrug resistance by selectively modulating drug efflux-related and -unrelated phenotypes, though further studies are necessary to deep its mechanisms of action.