An In Vitro Examination of Whether Kratom Extracts Enhance the Cytotoxicity of Low-Dose Doxorubicin against A549 Human Lung Cancer Cells

Sep 22, 2026

Doxorubicin is an effective chemotherapeutic agent for solid and hematological carcinomas, but long-term use can cause adverse effects and contribute to cancer cell resistance. This study evaluates whether A549 human lung cancer cells become more sensitive to low-dose doxorubicin (0.1 ppm) when combined with 10–60 ppm crude or alkaloid extracts from Kratom leaves. Crude extract showed limited effects due to low mitragynine content (4–5%), while alkaloid extract (40–45% MG) moderately inhibited cells with IC50 values of 48–55 ppm and promoted apoptosis. Combination treatments increased sensitivity 1.3–2.4 times (crude) or 2.6–3.4-fold (alkaloid), with combination indices of 0.6 and 0.3, indicating potential synergy. The findings suggest Kratom non-alkaloids may influence biological activity and support strategies to reduce doxorubicin dosage.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Abstract

Introduction

Doxorubicin adverse effects and limitations

Rationale for combination chemotherapy

molecules Article An In Vitro Examination of Whether Kratom Extracts Enhance the Cytotoxicity of Low-Dose Doxorubicin against A549 Human Lung Cancer Cells Asep Bayu 1, *, Siti Irma Rahmawati 1, Firmansyah Karim 1, Jonathan Ardhianto Panggabean 1, Dasilva Primarindu Nuswantari 1, Dwi Wahyu Indriani 1, Peni Ahmadi 1, Rendi Witular 2, Ni Luh Putu Indi Dharmayanti 3 and Masteria Yunovilsa Putra 1, * Citation: Bayu, A.; Rahmawati, S.I.; Karim, F.; Panggabean, J.A.; Nuswantari, D.P.; Indriani, D.W.; Ahmadi, P.; Witular, R.; Dharmayanti, N.L.P.I.; Putra, M.Y. An In Vitro Examination of Whether Kratom Extracts Enhance the Cytotoxicity of Low-Dose Doxorubicin against A549 Human Lung Cancer Cells. Molecules 2024, 29, 1404. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/molecules29061404](10.3390/molecules29061404) [Academic Editors: Elz](Academic Editors: Elz)˙ bieta Studzi ´nska-Sroka and Aleksandra Majchrzak-Celi ´nska Received: 8 February 2024 Revised: 18 March 2024 Accepted: 18 March 2024 Published: 21 March 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Research Center for Vaccine and Drugs, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor KM 46, Cibinong, Bogor 16911, Indonesia; [siti.irma.rahmawati@brin.go.id](siti.irma.rahmawati@brin.go.id) (S.I.R.); firmansyahkarim93@gmail.com (F.K.); jonathanardhianto@gmail.com (J.A.P.); [dasilvarindu@gmail.com](dasilvarindu@gmail.com) (D.P.N.); [dwiw007@brin.go.id](dwiw007@brin.go.id) (D.W.I.); [peni.ahmadi@brin.go.id](peni.ahmadi@brin.go.id) (P.A.) 2 Ministry of Health, Republic of Indonesia, Jalan HR Rasuna Said Blok X5 Kavling 4-9, Kuningan, South Jakarta 12950, Indonesia; [rendyaw@yahoo.com](rendyaw@yahoo.com) 3 Research Organization for Health, National Research and Innovation Agency (BRIN), Jalan Raya Jakarta-Bogor KM. 46, Cibinong, Bogor 16911, Indonesia; [nilu011@brin.go.id](nilu011@brin.go.id) * Correspondence: [asep044@brin.go.id](asep044@brin.go.id) (A.B.); [masteria.yunovilsa.putra@brin.go.id](masteria.yunovilsa.putra@brin.go.id) (M.Y.P.) Abstract: Doxorubicin is an effective chemotherapeutic agent in the treatment of solid hematological and non-hematological carcinoma. However, its long-term usage could result in side effects, such as cardiomyopathy, chronic heart failure, neurotoxicity and cancer cell resistance. In this study, we reported the sensitivity enhancement of A549 human lung cancer cells on doxorubicin at a low dose (0.1 ppm) in combination with 10–60 ppm of crude and alkaloid extracts derived from the leaves of Kratom (Mitragyna speciosa (Korth.) Havil. Rubiaceae) . A549 cancer cell lines were insensitive to the crude extract containing low mitragynine (MG) (4–5%), while these cells were moderately inhibited by the alkaloid extract containing 40–45% MG (IC 50 of 48–55 ppm) . The alkaloid extract was found to inhibit A549 cancer cells via apoptosis as suggested by the higher relative fluorescence intensity with Annexin compared to that in propidium iodide (PI), i.e., a positive Annexin and a negative PI. The combination of crude extract and doxorubicin sensitized A549 cancer cells to doxorubicin by 1.3 to 2.4 times, while the combination with the alkaloid induced a 2.6-to 3.4-fold increase in sensitivity. The calculated combination index (CI) for doxorubicin with the crude and alkaloid extracts was 0.6 and 0.3, respectively, showing potential synergistic combinations to reduce the level of dosage of doxorubicin used in chemotherapy. In addition, the synergistic enhancement effect of crude extract on the cytotoxic activity of doxorubicin provides insights into the plausibility

FAQs

What is the main objective of this study?

To determine whether Kratom extracts enhance the cytotoxicity of low-dose doxorubicin against A549 human lung cancer cells.

How did the crude and alkaloid extracts differ in their effects on A549 cells?

A549 cells were insensitive to crude extract with low mitragynine (4–5%), while they were moderately inhibited by the alkaloid extract containing 40–45% mitragynine.

Did combining Kratom extracts with doxorubicin improve cancer cell sensitivity?

Yes. Crude extract plus doxorubicin increased sensitivity by about 1.3 to 2.4 times, and alkaloid extract plus doxorubicin increased sensitivity by about 2.6 to 3.4 times, with combination indices suggesting synergy.

Sep 22, 2026

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