N-Alkylated Monoterpene Indole Alkaloid Derivatives as Chemotherapy Adjuvants That Overcome P-glycoprotein-Mediated Multidrug Resistance

Sep 22, 2026

Chemotherapy efficacy is constrained by multidrug resistance driven by P-glycoprotein (P-gp). This study evaluated N-alkylated dregamine and tabernaemontanine derivatives as adjuvants to counter P-gp–mediated chemoresistance. Twenty-one derivatives were tested in DOX-resistant ovarian and breast cancer cell lines and in hRPTEC, using rhodamine 123 accumulation and a Pgp-Glo assay for P-gp modulation. The leading compound N-(4-methoxybenzyl) dregamine enhanced DOX sensitivity in 2D and 3D tumor models, including patient-derived colorectal cancer organoids, without increased toxicity in healthy kidney epithelial cells or PBMCs, and docking supported mechanism.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages24

Reading Time1 h 0 min

AccessFree to download

Purpose

Patients and Methods

Cell models and P-gp modulation

3D spheroids, PDOs, and PBMCs

Computational docking

Results

Conclusion

Plain Language Summary

Drug Design, Development and Therapy Open Access Full Text Article ORIGINAL RESEARCH N-Alkylated Monoterpene Indole Alkaloid Derivatives as Chemotherapy Adjuvants That Overcome P-glycoprotein-Mediated Multidrug Resistance in Cancer Cells, Spheroids and Patient-Derived Colorectal Cancer Organoids Tomáš Nejedlý 1 , Ondřej Strnad 1 , Jan Ulrych2 , 3 , Václav Hanžl 1 , Ivana Křížová 4 , Simona Dobiasová 1 , 5 , David Paulino Cardoso 6 , Silva F Mulhovo 7 , Markéta Častorálová 1 , MariaJosé U Ferreira 6 , Jitka Viktorová 1 1Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague, Czechia; 2 1st Department of Surgery – Department of Abdominal, Thoracic Surgery and Traumatology, General University Hospital in Prague, Prague, Czechia; 3First Faculty of Medicine, Charles University, Prague, Czechia; 4Department of Biotechnology, University of Chemistry and Technology, Prague, Czechia; 5Molecular Biotechnology Center “Guido Tarone”, Department of Oncology, University of Turin, Turin, Italy; 6Research Institute for Medicines (iMed. ULisboa), University of Lisbon, Lisbon, Portugal; 7Centro de Estudos Moçambicanos e de Etnociências (CEMEC), Universidade Pedagógica Campus de Lhanguene, Maputo, Mozambique Correspondence: Jitka Viktorová, Department of Biochemistry and Microbiology, University of Chemistry and Technology, Technická 3, Prague, 166 28, Czechia, [Email prokesoj@vscht.cz](Email prokesoj@vscht.cz) Purpose: Chemotherapy efficacy is often limited by multidrug resistance (MDR), largely driven by P-glycoprotein (P-gp) . This study aimed to evaluate previously prepared N-alkylated dregamine and tabernaemontanine derivatives as potential adjuvants to overcome P-gp–mediated chemoresistance. Patients and Methods: Twenty-one N-alkylated derivatives (1–21) were tested for cytotoxicity and chemosensitizing activity insensitive and doxorubicin (DOX)-resistant ovarian (A2780, A2780DOX) and breast cancer cell lines (MCF-7, MCF-7R), as well as in nonmalignant kidney epithelial cells (hRPTEC). P-gp modulation was assessed using rhodamine 123 accumulation and Pgp-Glo Assay Systems kit. The activity of the most promising compound was further evaluated in 3D monocellular and multicellular spheroids, patient-derived colorectal cancer organoids (PDOs), and peripheral blood mononuclear cells (PBMCs) . Computational docking was performed to support mechanistic insights. Results: The derivatives exhibited moderate cytotoxicity toward cancer cells and low toxicity toward hRPTEC. All compounds sensitized resistant cell lines, with the most active ones reducing DOX IC50 by >20-fold at 10 μM and >8-fold at 1 μM. For most derivatives, increased accumulation of rhodamine 123 confirmed modulation of P-gp efflux activity. N-(4-methoxybenzyl) dregamine (compound 11) showed the strongest potential, enhancing DOX sensitivity >7-fold in monocellular and >4-fold in multicellular spheroids. In combination with DOX, compound 11 also increased the sensitivity of colorectal cancer PDOs, thereby reducing their viability from 70% to 30% . No increased toxicity of DOX was observed in PBMCs. Conclusion: N-alkylated monoterpene–indole alkaloids, particularly compound 11, effectively overcome P-gp–mediated chemoresistance without inducing cytotoxicity in healthy cells and represent promising candidates for further in vivo evaluation. Plain Language Summary: Cancer cells can become resistant to treatment in several ways. One common mechanism is the increased production of protective proteins. One such protein, P-glycoprotein (P-gp), works like a pump that removes chemotherapy drugs from inside cancer cells, making treatment less effective. A possible solution is to block P-gp activity. However, earlier P-gp inhibitors tested in clinical trials were too toxic and failed. This study therefore focused on new compounds derived from natural substances called dregamine and tabernaemontanine, isolated from the African plant Tab

FAQs

What problem does the study target in cancer chemotherapy?

The study targets multidrug resistance caused by P-glycoprotein (P-gp), which reduces chemotherapy effectiveness by pumping drugs out of cancer cells.

How were the N-alkylated derivatives evaluated in this research?

Twenty-one derivatives were tested for cytotoxicity and chemosensitizing activity in DOX-resistant and sensitive ovarian/breast cancer cell lines, as well as in hRPTEC. P-gp modulation was assessed using rhodamine 123 accumulation and a Pgp-Glo assay.

Which compound showed the strongest potential, and what were its effects?

N-(4-methoxybenzyl) dregamine (compound 11) showed the strongest potential, increasing DOX sensitivity in monocellular and multicellular spheroids and in patient-derived colorectal cancer organoids, while not increasing toxicity in PBMCs.

Sep 22, 2026

Upload by Clementine