Research ArticleExperimental Studies
Open Access

Low-dose Andrographolide Synergizes With Cytarabine or Vincristine in Plasma Cell Neoplasm Cell Lines

HIROKI DOI, HIDEHIKO AKIYAMA, TAEI MATSUI, YUKO ABE, SUMIE FUJII, HIDEAKI MATSUURA and YASUO MIURA
Anticancer Research June 2026, 46 (6) 3067-3077; DOI: https://doi.org/10.21873/anticanres.18181

Abstract

Background/Aim: Andrographolide (Andro), a diterpene lactone from Andrographis paniculata, induces apoptosis via reactive oxygen species (ROS)-dependent mitochondrial dysfunction but achieves low plasma concentrations because of its lipophilicity. We investigated whether low-dose Andro potentiates the cytotoxicity of the mechanistically distinct agents cytarabine (Ara-C) and vincristine (VCR) in plasma cell neoplasm cell lines.

Materials and Methods: Human plasma cell neoplasm cell lines H929 and ARH77 were treated with Andro alone or in combination with Ara-C or VCR. Cell viability was assessed in dose- and time-response experiments, and pharmacologic interactions were quantified using the combination index (CI) method. Apoptosis was evaluated by Annexin V staining, and cell-cycle distribution was analyzed to examine mechanistic complementarity.

Results: Andro decreased viability in a dose- and time-dependent manner (IC50 at 48 h: 3.4 μM in H929; 7.5 μM in ARH77). Combining Andro with Ara-C or VCR further reduced viability; in H929 cells, all combination conditions yielded CI values <1.0, indicating synergy. Combination treatments markedly increased Annexin V-positive fractions, implicating apoptosis as a major contributor to enhanced cytotoxicity. While Andro alone did not appreciably alter cell-cycle profiles, it modestly influenced Ara-C- and VCR-associated changes in cell-cycle distribution, consistent with complementary mechanisms.

Conclusion: Low-dose Andro strengthens Ara-C- and VCR-driven cytotoxic programs and provides a quantitative rationale for Andro-based combination strategies in plasma cell neoplasms and related hematologic malignancies.

Keywords:

Introduction

Cytosine β-D-arabinofuranoside (cytarabine, Ara-C) is a synthetic pyrimidine nucleoside analogue widely used in the treatment of hematologic malignancies (1, 2). Following cellular uptake through nucleoside transporters, it is phosphorylated by deoxycytidine kinase to form Ara-CTP, which competes with dCTP for DNA incorporation, inhibits DNA polymerase, and terminates chain elongation, thereby blocking DNA synthesis and arresting cells in the S phase (3-5). Vincristine (VCR), a vinca alkaloid derived from Catharanthus roseus, binds β-tubulin and prevents microtubule polymerization, disrupting mitotic spindle formation and arresting cells at metaphase (6, 7). Both Ara-C and VCR are cytotoxic agents but lack tumor selectivity (8), leading to collateral injury of rapidly proliferating normal tissues (6, 8).

Andrographolide (Andro), a diterpene lactone isolated from Andrographis paniculata (9, 10), induces apoptosis through reactive oxygen species (ROS)–dependent mitochondrial dysfunction, leading to loss of membrane potential, cytochrome c release, and caspase activation (11). In leukemia and solid-tumor models, Andro-induced apoptosis is attenuated by the ROS scavenger N-acetyl-L-cysteine, implicating ROS/JNK signaling in its cytotoxicity (12-14). In contrast to the S-phase– and M-phase–dependent actions of Ara-C and VCR, Andro exerts cell cycle–independent cytotoxicity. This mechanistic distinction provides a rationale for combining Andro with phase–specific cytotoxic agents to achieve synergistic effects while potentially reducing systemic toxicity. In our previous analyses, Andro treatment did not alter cell cycle distribution in leukemia cell lines (11, 12). Based on these findings, the present study examined whether the cell cycle–independent Andro could synergize with the cell cycle–dependent agents Ara-C or VCR to induce apoptosis in plasma cell leukemia models.

Materials and Methods

Cell lines and reagents. NCI-H929 cell (human IgA-κ–producing multiple myeloma cell line; ECACC: 95050415; RRID: CVCL_1600) and ARH77 cell (human IgG–producing plasma cell lineage-related cell line; ECACC: 88121201; RRID: CVCL_1072) were obtained from DS Pharma Biomedical (Osaka, Japan). Cells were cultured in RPMI-1640 (Sigma-Aldrich, St. Louis, MO, USA) supplemented with 10% heat-inactivated fetal bovine serum (FBS; Equitech-Bio Inc., Kerrville, TX, USA), 100 U/ml penicillin (Gibco/Thermo Fisher Scientific, Carlsbad, CA, USA), and 100 μg/ml streptomycin (Gibco/Thermo Fisher Scientific) at 37°C in a humidified atmosphere containing 5% CO2. Andro (Tokyo Chemical Industry, Tokyo, Japan), Ara-C (Sigma-Aldrich), and VCR (Sigma-Aldrich) were dissolved in dimethyl sulfoxide (DMSO) to prepare stock solutions and stored at −20°C. The final DMSO concentration in all culture conditions did not exceed 1.0%.

Cell viability assay. Cells (3×104 per well) were seeded in 96-well plates and treated for 24 or 48 h with graded concentrations of Andro (0-50 μM), Ara-C (0-200 μM), VCR (0-0.50 μM), or their combinations as specified. After incubation, MTT reagent (Cayman Chemical, Ann Arbor, MI, USA) was added, and the plates were incubated for an additional 4 h. The resulting formazan was solubilized in crystal dissolving solution, and absorbance was measured at 570 nm. Cell viability was calculated as follows:

Embedded Image

Combination index, dose-reduction index, and isobologram analysis. The IC50 values, combination index (CI), and dose-reduction index (DRI) were calculated using CompuSyn software (ComboSyn Inc., Paramus, NJ, USA). CI values <1.0, 1.0, and >1.0 indicate synergistic, additive, and antagonistic effects, respectively. DRI values >1.0 denote a favorable dose-reduction potential for each agent in the combination, indicating the degree to which the dose can be reduced at a given effect level owing to synergism (15-17). Isobolograms were generated automatically by CompuSyn to visualize the interaction pattern.

Apoptosis assay. H929 cells were seeded in 24-well plates and treated for 24-48 h with Andro (3 μM), Ara-C (20 or 40 μM), VCR (0.03 μM), or the corresponding combinations. Apoptosis was assessed using the Muse Annexin V and Dead Cell Assay Kit (Merck Millipore, Burlington, MA, USA) on a Muse Cell Analyzer (Merck Millipore) according to the manufacturer’s instructions as previously described (11).

Cell cycle analysis. H929 cells were seeded in 6-well plates at a density of 5×105 cells/ml and treated for 24-48 h under the same conditions as in the apoptosis assay. After treatment, cell cycle distribution was assessed using the Muse Cell Cycle Kit (Merck Millipore) on a Muse Cell Analyzer (Merck Millipore) according to the manufacturer’s instructions as previously described (11).

Statistical analysis. Statistical analyses were performed using EZR, a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) as previously described (11). Cell viability, apoptosis, and cell cycle assays were performed in triplicate as three independent biological experiments. Results are expressed as mean ± SD of independent experiments. Comparisons between two groups were performed using Student’s t-test, and one-way ANOVA was applied for comparisons among three or more groups. A p-value <0.05 was considered statistically significant.

Results

Andro decreases H929 and ARH77 cell viability and further reduces viability when combined with Ara-C or VCR. Using the MTT assay after 24 and 48 h of incubation, Andro and VCR reduced H929 and ARH77 cell viability in a dose- and time-dependent manner (Figure 1a-d). In H929 cells, the IC50 of Andro declined from 7.1 μM at 24 h to 3.4 μM at 48 h, and that of VCR from 0.31 μM to 0.02 μM, indicating increased potency over time. In contrast, Ara-C showed limited reduction in viability at 24 h in H929 cells, and an IC50 could not be reliably determined within the tested concentration range. At 48 h, however, Ara-C produced a greater reduction in viability (IC50=5.3 μM), suggesting a delayed onset of effect. In ARH77 cells, the IC50 of Andro declined from 10.3 μM at 24 h to 7.5 μM at 48 h, and VCR also showed increased potency over time. Ara-C reduced viability at 48 h in ARH77 cells. However, because curve fitting estimated an IC50 near or below the lowest concentration tested, this value should be interpreted cautiously. Across most tested conditions, the combination curves for Andro + Ara-C (orange dashed) and Andro + VCR (blue dashed) tended to be lower than the corresponding single-agent curves, indicating enhanced reduction in cell viability in most, but not all, settings. Exceptions were observed in ARH77 cells at 48 h, including Andro 3 μM + Ara-C 12 μM, Andro 5 μM + Ara-C 20 μM, and Andro 10 μM + Ara-C 40 μM. This effect was more apparent at 48 h in H929 cells than in ARH77 cells (Figure 1a-d).

Figure 1.
Figure 1.

Effects of Andro, Ara-C, VCR, and their combinations on H929 and ARH77 cell viability measured by MTT assay. Cell viability was assessed after 24 h (a, c) and 48 h (b, d) of treatment in H929 and ARH77 cells. Panels (a) and (b) show the results for H929 cells at 24 h and 48 h, respectively, whereas panels (c) and (d) show the corresponding results for ARH77 cells. Solid lines indicate single-agent treatments, with Andro shown in green, Ara-C in orange, and VCR in blue, whereas dashed lines indicate combination treatments, with Andro + Ara-C shown as an orange dashed line and Andro + VCR shown as a blue dashed line. The y-axis represents viability (%) calculated from MTT absorbance relative to the control group (set to 100%). Results are expressed as mean ± SD of three independent experiments.

Low-dose Andro exhibits synergistic cytotoxicity with Ara-C or VCR in H929 and ARH77 cells. Cell viability was further evaluated using Andro (3 μM) in combination with Ara-C (12-40 μM) or VCR (0.03-0.10 μM). At both 24 and 48 h, each combination treatment reduced cell viability more than Andro alone. In H929 cells, all combinations yielded CI values <1.0, indicating pharmacologic synergy. In ARH77 cells, CI values were <1.0 for most combinations; however, Andro (3 μM) + Ara-C (12 μM) and Andro (3 μM) + Ara-C (40 μM) at 48 h showed CI values >1.0, indicating antagonism (Table I). Isobologram analysis further supported these findings, with the exception of Andro (3 μM) + Ara-C (12 μM) and Andro (3 μM) + Ara-C (40 μM) at 48 h in ARH77 cells, all combination points falling below the line of additivity, consistent with synergistic interactions (Figure 2a-h). In ARH77 cells at 48 h, the point for Andro (3 μM) + Ara-C (12 μM) is not shown in the normalized isobologram generated by CompuSyn because the combination index was relatively large, causing the corresponding point to fall outside the plotting range of the software output (Figure 2g).

View this table:
Table I.

Synergistic effects of Andro in combination with Ara-C or VCR in H929 and ARH77 cells.

Figure 2.
Figure 2.

Isobologram analysis of combined treatment with Andro and Ara-C or VCR in H929 and ARH77 cells. Isobolograms show the interactions between Andro and Ara-C or VCR in H929 cells at 24 (a, b) and 48 h (c, d), and in ARH77 cells at 24 (e, f) and 48 h (g, h) of incubation. The numbered points correspond to the following drug combinations: For H929 and ARH77 cells: (1) Andro (3 μM) + Ara-C (12 μM); (2) Andro (3 μM) + Ara-C (20 μM); (3) Andro (3 μM) + Ara-C (40 μM); (4) Andro (3 μM) + VCR (0.03 μM); (5) Andro (3 μM) + VCR (0.05 μM); (6) Andro (3 μM) + VCR (0.1 μM). The solid diagonal line represents the theoretical line of additivity [combination index (CI)=1.0]; points below the line indicate synergistic interactions (CI<1.0).

Consistent with the CI values, in H929 cells at 24 h, the strongest synergistic effects were observed with Andro (3 μM) + Ara-C (40 μM) and Andro (3 μM) + VCR (0.03 μM), producing 42.6% and 52.8% cytotoxicity with CI values of 0.544 and 0.459, respectively. At 48 h, the most pronounced synergy was observed with Andro (3 μM) + Ara-C (20 μM) and Andro (3 μM) + VCR (0.03 μM), yielding 76.7% and 80.7% cytotoxicity with CI values of 0.255 and 0.346, respectively. In ARH77 cells at 24 h, the strongest synergistic effects were observed with Andro (3 μM) + Ara-C (20 μM) and Andro (3 μM) + VCR (0.05 μM), producing 60.2% and 69.8% cytotoxicity with CI values of 0.295 and 0.451, respectively. At 48 h, the most pronounced synergy was observed with Andro (3 μM) + Ara-C (20 μM) and Andro (3 μM) + VCR (0.03 μM), yielding 86.6% and 86.8% cytotoxicity with CI values of 0.866 and 0.330, respectively. These quantitative analyses demonstrate that low-dose Andro synergistically enhances cytotoxicity of Ara-C and VCR in H929 and ARH77 cells.

Combination of low-dose Andro with Ara-C or VCR enhances apoptosis in H929 cells. After 24 h, untreated H929 cells showed 15.1% Annexin V–positive cells (Figure 3a and b). Treatment with Andro (3 μM), Ara-C (40 μM), or VCR (0.03 μM) increased the proportion of Annexin V–positive cells to 19.7%, 27.2%, and 31.4%, respectively. The combination treatments produced still higher levels of Annexin V positivity. Specifically, Andro + Ara-C increased the proportion of Annexin V-positive cells to 41.6%, which was approximately 2.1-fold higher than that observed with Andro alone, whereas Andro + VCR increased it to 42.6%, corresponding to an approximately 2.2-fold increase relative to Andro alone. At 48 h, the same overall trend persisted. Compared with untreated controls, the combination treatments showed clearly higher Annexin V-positive fractions, and compared with the corresponding single-agent treatments, they generally showed higher levels of apoptosis (Figure 3h-n). Thus, the magnitude of increase in Annexin V positivity depended on the reference group and time point. These results suggest that the enhanced reduction in cell viability observed in the MTT assay is mediated, at least in part, by enhanced apoptosis.

Figure 3.
Figure 3.

Analysis of apoptosis induced by Andro, Ara-C, VCR, or their combinations in H929 cells. Apoptosis was assessed by Annexin V/7-AAD staining after 24 (a-g) and 48 h (h-n) of incubation. Cells were treated with Andro (3 μM), Ara-C (40 μM at 24 h; 20 μM at 48 h), VCR (0.03 μM), or their respective combinations. Results are expressed as mean ± SD of three independent experiments (a, h). Statistical analysis was performed using one-way ANOVA with Bonferroni’s multiple comparison test (*p<0.05, **p<0.01, ***p<0.001). Representative dot plots from the Muse Cell Analyzer are shown (b-g, i-n).

Andro modulates Ara-C– and VCR–associated changes in cell-cycle distribution in H929 cells. To determine whether the observed synergy was associated with altered cell-cycle dynamics, we analyzed phase distribution under the most synergistic conditions–Andro (3 μM) with Ara-C (40 μM at 24 h, 20 μM at 48 h) or VCR (0.03 μM at both time points) (Figure 4a-f). In untreated H929 cells, approximately half of the population was in the G0/G1 phase, accounting for 53.2% at 24 h and 59.2% at 48 h. The S-phase fraction accounted for 12.4% at 24 h and 16.3% at 48 h, whereas the G2/M fraction comprised 34.3% at 24 h and 24.4% at 48 h.

Figure 4.
Figure 4.

Cell cycle distribution of H929 cells treated with Andro, Ara-C, VCR, or their combinations. Cell cycle profiles were measured after treatment with Andro (3 μM), Ara-C (40 μM at 24 h, 20 μM at 48 h), or VCR (0.03 μM at both time points) for 24 (a-c) and 48 h (d-f) using the Muse Cell Analyzer. Panels show the percentages of cells in G0/G1 (blue; a, d), S (purple; b, e), and G2/M (green; c, f) -phases. Results are expressed as mean ± SD of three independent experiments. Statistical analysis was performed using one-way ANOVA with Bonferroni’s multiple comparison test (n.s. not significant; *p<0.05, **p<0.01, ***p<0.001).

Ara-C shifted the population toward the G0/G1 phase, increasing this fraction to 63.2% at 24 h and 70.7% at 48 h (Figure 4a and d). Correspondingly, the G2/M fraction decreased to 24.4% at 24 h and 14.2% at 48 h (Figure 4c and f), a pattern compatible with altered cell-cycle progression following Ara-C treatment (Figure 4b and e). In contrast, VCR showed the opposite tendency, decreasing the G0/G1 fraction to 43.1% at 24 h and 43.9% at 48 h (Figure 4a and d), while increasing the G2/M fraction to 43.6% at 24 h and 35.1% at 48 h (Figure 4c and f), consistent with mitotic arrest. Andro alone (3 μM) caused only modest changes in phase distribution, with no statistically significant effect (Figure 4a and d).

Combining Andro with Ara-C produced only a slight additional increase in the G0/G1 fraction compared with Ara-C alone at 48 h (71.2% vs. 70.7%), and this difference was not significant (Figure 4d). By contrast, the combination of Andro with VCR increased the G2/M fraction to 47.9% at 48 h compared with 35.1% for VCR alone, and this difference was significant. At 24 h, however, the corresponding increase (47.0% vs. 43.6%) did not reach statistical significance (Figure 4c and f). Collectively, Ara-C was associated with a shift toward G0/G1, whereas VCR increased the G2/M fraction, while Andro alone produced little redistribution. Under synergistic conditions, Andro did not markedly alter the overall cell-cycle profile by itself but may have modestly influenced the phase-specific effects associated with Ara-C and VCR.

Discussion

In this study, we demonstrated that low-dose Andro, when combined with the commonly used cytotoxic agents Ara-C or VCR, synergistically reduced cell viability in H929 and ARH77 plasma cell neoplasm cells. Across most tested concentrations, the combination treatments showed lower cell viability than the corresponding single-agent conditions at both 24 and 48 h, with the reduction being more pronounced at 48 h, particularly in H929 cells. Quantitative interaction analysis using the Chou–Talalay method further supported this interpretation, exhibiting synergistic interactions across all combination conditions in H929 cells, with the strongest effects observed for Andro (3 μM) and Ara-C (20 μM) and Andro (3 μM) and VCR (0.03 μM) at 48 h. These results indicate that the magnitude of synergy increased over time, reinforcing the concept that Andro augments the cytotoxic programs initiated by S-phase inhibition or mitotic arrest.

According to pharmacokinetic data, the steady-state plasma concentration of Andro in humans reaches approximately 1.9 μM after an oral intake of 1 mg/kg/day (18). Moreover, Andro exhibited antiproliferative activity against H929 and ARH77 cells even at low concentrations (1-10 μM), with an IC50 of 7.1 and 10.3 μM, within clinically reported plasma concentration levels. Although its plasma concentration is limited by its lipophilic and poorly water-soluble nature (19), a concentration of 3 μM still produced clear synergism (CI <1.0) when combined with Ara-C or VCR. These findings suggest that low-dose Andro may complement conventional cytotoxic drugs and motivate further examination of its combination effects.

In contrast to the consistently synergistic interactions observed in H929 cells, ARH77 cells exhibited antagonistic interactions under specific combination conditions, most notably at 48 h with Andro (3 μM) combined with Ara-C (12 μM or 40 μM). This divergence suggests that the extent of pharmacologic cooperativity between Andro and Ara-C is context-dependent and influenced by intrinsic cellular sensitivity to Ara-C (1, 3, 4). One plausible explanation for this antagonism is a ceiling effect arising from the high intrinsic susceptibility of ARH77 cells to Ara-C at later time points. Under such near-saturating conditions, the addition of Andro may confer only limited incremental cytotoxic benefit, resulting in CI values greater than 1 despite substantial overall cell death.

In H929 cells, the mechanistic basis of the observed synergy appears to involve a convergence of apoptosis induction and the amplification of phase-specific cytotoxic programs. Annexin V/7-AAD analysis demonstrated that Andro alone induced only modest apoptosis, whereas its combination with Ara-C or VCR consistently increased the apoptotic fraction beyond that achieved by either single agent. This enhancement was greater at 48 h than at 24 h, indicating that Andro not only augments the initial apoptotic response triggered by S-phase inhibition or mitotic arrest but also reinforces its execution over time. These findings support the interpretation that apoptosis contributes substantially to the synergistic loss of viability observed in the MTT assay. Although apoptosis appears to be the dominant contributor, we cannot exclude additional non-apoptotic mechanisms, such as oxidative stress–related cell death, which warrant future investigation.

In H929 cells, cell-cycle analysis further clarified the nature of this interaction. Ara-C increased the G0/G1 population, compatible with altered cell-cycle progression following Ara-C treatment, whereas VCR induced G2/M arrest through disruption of microtubule dynamics. In contrast, Andro alone did not significantly alter cell-cycle distribution, indicating that its pro-apoptotic effects occur largely independently of canonical cell-cycle checkpoints. This is consistent with previous reports describing Andro-induced apoptosis through cell-cycle–independent pathways, potentially involving mitochondrial oxidative stress (11). Previous studies suggest that Andro promotes apoptosis via oxidative stress- and mitochondria-related mechanisms (20, 21). Such a mechanism provides a coherent explanation for the complementary effects observed in the combination settings: Andro can engage apoptosis without relying on S-phase or M-phase arrest, thereby potentially augmenting the cytotoxic programs initiated by Ara-C and VCR.

Together, these observations suggest that the synergy arises from a dual mechanism in which Andro enhances apoptosis while concurrently modestly influencing the phase-associated cytotoxic effects of Ara-C and VCR, resulting in a more robust execution of cell death than either pathway alone could achieve.

The strongest synergistic interactions with VCR were observed at the lowest tested concentration (0.03 μM), rather than at higher doses. This pattern may reflect how VCR engages mitotic checkpoints and apoptosis across its dose range. VCR induces G2/M arrest in a highly dose-sensitive manner, such that even low concentrations are sufficient to trigger mitotic blockade, whereas higher concentrations approach maximal levels of apoptosis, leaving limited capacity for additional cooperative effects with Andro (ceiling effect). Moreover, cells arrested in mitosis are intrinsically more vulnerable to mitochondrial oxidative stress (22), raising the possibility that low-dose VCR – enriching, but not saturating, the G2/M population – creates a cellular context in which Andro’s pro-apoptotic signaling is particularly effective. Together, these considerations provide a plausible explanation for why lower VCR concentrations yield more pronounced synergistic effects when combined with Andro in our system.

Conclusion

Low-dose Andro synergistically enhanced the cytotoxic effects of Ara-C or VCR in plasma cell neoplasm cell lines, particularly in H929 cells, as quantified by combination index analysis. Mechanistically, the combinations increased apoptosis and were associated with modest modulation of the cell-cycle changes induced by Ara-C and VCR, consistent with complementary, phase-specific cytotoxic programs. Although antagonism was observed in ARH77 cells under selected Ara-C combinations at 48 h, these findings provide a quantitative rationale for further exploring Andro-based combination strategies in plasma cell neoplasms and related hematologic malignancies.

Acknowledgements

This work was supported by Fujita Health University.

Footnotes

  • Authors’ Contributions

    H.D., H.A., T.M. and Y.M. conceived, and designed the research, Y.A. and S.F. performed flow cytometry and statistical analysis of the experiments, H.M. analyzed the data. H.D. wrote the original draft. Y.M. reviewed and edited the manuscript. All authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare that they have no financial or nonfinancial competing interests.

  • Funding

    This work was supported by JSPS KAKENHI Grants Number JP25K18200 to Hiroki Doi.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received February 13, 2026.
  • Revision received March 10, 2026.
  • Accepted April 3, 2026.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

References

  1. ↵
    1. Galmarini CM,
    2. Mackey JR,
    3. Dumontet C
    : Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia 15(6): 875-890, 2001. DOI: 10.1038/sj.leu.2402114
    OpenUrlCrossRefPubMed
  2. ↵
    1. Faruqi A,
    2. Tadi P
    : Cytarabine. Treasure Island, FL, USA, StatPearls Publishing, 2025.
  3. ↵
    1. Hubeek I,
    2. Stam RW,
    3. Peters GJ,
    4. Broekhuizen R,
    5. Meijerink JP,
    6. van Wering ER,
    7. Gibson BE,
    8. Creutzig U,
    9. Zwaan CM,
    10. Cloos J,
    11. Kuik DJ,
    12. Pieters R,
    13. Kaspers GJ
    : The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia. Br J Cancer 93(12): 1388-1394, 2005. DOI: 10.1038/sj.bjc.6602881
    OpenUrlCrossRefPubMed
  4. ↵
    1. Di Francia R,
    2. Crisci S,
    3. De Monaco A,
    4. Cafiero C,
    5. Re A,
    6. Iaccarino G,
    7. De Filippi R,
    8. Frigeri F,
    9. Corazzelli G,
    10. Micera A,
    11. Pinto A
    : Response and toxicity to cytarabine therapy in leukemia and lymphoma: from dose puzzle to pharmacogenomic biomarkers. Cancers (Basel) 13(5): 966, 2021. DOI: 10.3390/cancers13050966
    OpenUrlCrossRefPubMed
  5. ↵
    1. Sampath D,
    2. Cortes J,
    3. Estrov Z,
    4. Du M,
    5. Shi Z,
    6. Andreeff M,
    7. Gandhi V,
    8. Plunkett W
    : Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. Blood 107(6): 2517-2524, 2006. DOI: 10.1182/blood-2005-08-3351
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Jordan MA,
    2. Wilson L
    : Microtubules as a target for anticancer drugs. Nat Rev Cancer 4(4): 253-265, 2004. DOI: 10.1038/nrc1317
    OpenUrlCrossRefPubMed
  7. ↵
    1. Škubník J,
    2. Pavlíčková VS,
    3. Ruml T,
    4. Rimpelová S
    : Vincristine in combination therapy of cancer: emerging trends in clinics. Biology (Basel) 10(9): 849, 2021. DOI: 10.3390/biology10090849
    OpenUrlCrossRefPubMed
  8. ↵
    1. Wikramanayake TC,
    2. Haberland NI,
    3. Akhundlu A,
    4. Laboy Nieves A,
    5. Miteva M
    : Prevention and treatment of chemotherapy-induced alopecia: what is available and what is coming? Curr Oncol 30(4): 3609-3626, 2023. DOI: 10.3390/curroncol30040275
    OpenUrlCrossRefPubMed
  9. ↵
    1. Hossain R,
    2. Quispe C,
    3. Herrera-Bravo J,
    4. Beltrán JF,
    5. Islam MT,
    6. Shaheen S,
    7. Cruz-Martins N,
    8. Martorell M,
    9. Kumar M,
    10. Sharifi-Rad J,
    11. Ozdemir FA,
    12. Setzer WN,
    13. Alshehri MM,
    14. Calina D,
    15. Cho WC
    : Neurobiological promises of the bitter diterpene lactone andrographolide. Oxid Med Cell Longev 2022: 3079577, 2022. DOI: 10.1155/2022/3079577
    OpenUrlCrossRefPubMed
  10. ↵
    1. Zhang J,
    2. Li C,
    3. Zhang L,
    4. Heng Y,
    5. Wang S,
    6. Pan Y,
    7. Cai L,
    8. Zhang Y,
    9. Xu T,
    10. Chen X,
    11. Hoffman RM,
    12. Jia L
    : Andrographolide, a diterpene lactone from the Traditional Chinese Medicine Andrographis paniculate, induces senescence in human lung adenocarcinoma via p53/p21 and Skp2/p27. Phytomedicine 98: 153933, 2022. DOI: 10.1016/j.phymed.2022.153933
    OpenUrlCrossRefPubMed
  11. ↵
    1. Doi H,
    2. Akiyama H,
    3. Matsui T,
    4. Shiogama K,
    5. Hirayama M,
    6. Nakagawa R,
    7. Fujii S,
    8. Matsuura H,
    9. Miura Y
    : Andrographolide drives dual apoptosis and ferroptosis via caspase-3 and FACL4 in T-ALL cell lines. Int J Hematol 122(6): 843-855, 2025. DOI: 10.1007/s12185-025-04044-7
    OpenUrlCrossRef
  12. ↵
    1. Doi H,
    2. Matsui T,
    3. Dijkstra JM,
    4. Ogasawara A,
    5. Higashimoto Y,
    6. Imamura S,
    7. Ohye T,
    8. Takematsu H,
    9. Katsuda I,
    10. Akiyama H
    : Andrographolide, isolated from Andrographis paniculata, induces apoptosis in monocytic leukemia and multiple myeloma cells via augmentation of reactive oxygen species production. F1000Res 10: 542, 2021. DOI: 10.12688/f1000research.53595.3
    OpenUrlCrossRef
    1. Zhou J,
    2. Lu GD,
    3. Ong CS,
    4. Ong CN,
    5. Shen HM
    : Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation. Mol Cancer Ther 7(7): 2170-2180, 2008. DOI: 10.1158/1535-7163.MCT-08-0071
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Li J,
    2. Cheung HY,
    3. Zhang Z,
    4. Chan GK,
    5. Fong WF
    : Andrographolide induces cell cycle arrest at G2/M phase and cell death in HepG2 cells via alteration of reactive oxygen species. Eur J Pharmacol 568(1-3): 31-44, 2007. DOI: 10.1016/j.ejphar.2007.04.027
    OpenUrlCrossRefPubMed
  15. ↵
    1. Chou TC,
    2. Talalay P
    : Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur J Biochem 115(1): 207-216, 2005. DOI: 10.1111/j.1432-1033.1981.tb06218.x
    OpenUrlCrossRef
    1. Chou TC
    : Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58(3): 621-681, 2006. DOI: 10.1124/pr.58.3.10
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Pauwels B,
    2. Vermorken JB,
    3. Wouters A,
    4. Ides J,
    5. Van Laere S,
    6. Lambrechts HA,
    7. Pattyn GG,
    8. Vermeulen K,
    9. Meijnders P,
    10. Lardon F
    : The role of apoptotic cell death in the radiosensitising effect of gemcitabine. Br J Cancer 101(4): 628-636, 2009. DOI: 10.1038/sj.bjc.6605145
    OpenUrlCrossRefPubMed
  18. ↵
    1. Panossian A,
    2. Hovhannisyan A,
    3. Mamikonyan G,
    4. Abrahamian H,
    5. Hambardzumyan E,
    6. Gabrielian E,
    7. Goukasova G,
    8. Wikman G,
    9. Wagner H
    : Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine 7(5): 351-364, 2000. DOI: 10.1016/S0944-7113(00)80054-9
    OpenUrlCrossRefPubMed
  19. ↵
    1. Parveen R,
    2. Ahmad FJ,
    3. Iqbal Z,
    4. Samim M,
    5. Ahmad S
    : Solid lipid nanoparticles of anticancer drug andrographolide: formulation, in vitro and in vivo studies. Drug Dev Ind Pharm 40(9): 1206-1212, 2014. DOI: 10.3109/03639045.2013.810636
    OpenUrlCrossRefPubMed
  20. ↵
    1. Suwan N,
    2. Teerawongsuwan S,
    3. Jenjittikul S,
    4. Senaweenin Y,
    5. Watanapokasin R,
    6. Rungsiwiwut R
    : Andrographolide induces mitochondrial dysfunction and alters stemness-related gene expression in MCF7 breast cancer cells. Anticancer Res 46(1): 263-272, 2026. DOI: 10.21873/anticanres.17940
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Mongkon I,
    2. Kariya R,
    3. Pearngam P,
    4. Settha N,
    5. Saisuwan K,
    6. Boonnate P,
    7. Sittithumcharee G,
    8. Vaeteewoottacharn K,
    9. Saeeng R,
    10. Okada S
    : Andrographolide induces ROS-dependent apoptosis and suppresses STAT3 phosphorylation in primary effusion lymphoma cells. Anticancer Res 45(12): 5299-5311, 2025. DOI: 10.21873/anticanres.17869
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Patterson JC,
    2. Joughin BA,
    3. van de Kooij B,
    4. Lim DC,
    5. Lauffenburger DA,
    6. Yaffe MB
    : ROS and oxidative stress are elevated in mitosis during asynchronous cell cycle progression and are exacerbated by mitotic arrest. Cell Syst 8(2): 163-167.e2, 2019. DOI: 10.1016/j.cels.2019.01.005
    OpenUrlCrossRefPubMed
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Low-dose Andrographolide Synergizes With Cytarabine or Vincristine in Plasma Cell Neoplasm Cell Lines
HIROKI DOI, HIDEHIKO AKIYAMA, TAEI MATSUI, YUKO ABE, SUMIE FUJII, HIDEAKI MATSUURA, YASUO MIURA
Anticancer Research Jun 2026, 46 (6) 3067-3077; DOI: 10.21873/anticanres.18181
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