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. 2022 May 25;12(1):8858.
doi: 10.1038/s41598-022-11441-z.

The effect of apigenin and chemotherapy combination treatments on apoptosis-related genes and proteins in acute leukaemia cell lines

Amani A Mahbub  1 , Christine L Le Maitre  2 , Neil A Cross  2 , Nicola Jordan-Mahy  3
Affiliations

The effect of apigenin and chemotherapy combination treatments on apoptosis-related genes and proteins in acute leukaemia cell lines

Amani A Mahbub et al. Sci Rep. .

Abstract

Apigenin is a dietary polyphenol found abundantly in fruit and vegetables, which sensitizes leukaemia cells to topoisomerase inhibitor agents (e.g., etoposide), and alkylating agents (e.g., cyclophosphamide), reducing ATP levels and inducing apoptosis; whilst being protective to control haematopoietic stem cells. This study analysed the expression profiles of intrinsic and extrinsic apoptosis-related genes and proteins to help elucidate the mechanisms of action of apigenin when used in combination with etoposide or cyclophosphamide in lymphoid and myeloid leukaemia cell lines (Jurkat and THP-1). Expression of apoptosis-related genes were measured using a TaqMan® Human Apoptosis Array and the StepOne Plus RT-qPCR System, whilst apoptosis-related proteins were determined using a protein profiler™-human apoptosis array and the LI-COR OdysseyR Infrared Imaging System. Apigenin when combined with etoposide or cyclophosphamide-induced apoptosis via the mitochondrial pathway, increasing the expression of pro-apoptotic cytochrome c, SMAC/DIABLO, and HTRA2/OMI, which promoted caspase-9 and -3 activation. Targeting anti-apoptotic and/or pro-apoptotic members of the apoptotic pathways is a promising strategy to induce cancer cell death and improve sensitivity to chemotherapy agents. Here the apoptotic pathways induced by apigenin in combination with etoposide or cyclophosphamide were identified within human leukaemia cell lines, such applications could provide combination therapies for the treatment of leukaemia.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Effects of apigenin (AP) alone and in combination with etoposide (ETP) and cyclophosphamide (CYCLO) on expression of BCL2 and BCLX anti-apoptotic genes (A) and proteins (B) in acute myeloid (THP-1) and lymphoid (Jurkat) leukaemia cell lines when treated with their lowest significant doses (LSDs) that induce apoptosis (determined previously in Mahbub et al., 2013, 2015, 2019) for 24 h. Gene and protein data are expressed as medians and ranges. Results were considered statistically significant when P ≤ 0.05 (*). The combination treatment effects and colours were determined based on the statistical analysis described.
Figure 2
Figure 2
Effects of apigenin (AP) alone and in combination with etoposide (ETP) and cyclophosphamide (CYCLO) on expression of BAD and BAX pro-apoptotic genes (A) and proteins (B) in acute myeloid (THP-1) and lymphoid (Jurkat) leukaemia cell lines when treated with their lowest significant doses (LSDs) that induce apoptosis (determined previously in Mahbub et al., 2013, 2015, 2019) for 24 h. Gene and protein data are expressed as medians and ranges. Results were considered statistically significant when P ≤ 0.05 (*). The combination treatment effects and colours were determined based on the statistical analysis described in.
Figure 3
Figure 3
Effects of apigenin (AP) alone and in combination with etoposide (ETP) and cyclophosphamide (CYCLO) on expression of Cytochrome c (CYT c) mitochondrial gene (A) and protein (B) in acute myeloid (THP-1) and lymphoid (Jurkat) leukaemia cell lines when treated with their lowest significant doses (LSDs) that induce apoptosis (determined previously in Mahbub et al., 2013, 2015, 2019) for 24 h. Gene and protein data are expressed as medians and ranges. Results were considered statistically significant when P ≤ 0.05 (*). The combination treatment effects and colours were determined based on the statistical analysis described in.
Figure 4
Figure 4
Effects of apigenin (AP) alone and in combination with etoposide (ETP) and cyclophosphamide (CYCLO) on expression of SMAC/DIABLO and HTRA2/OMI mitochondrial genes (A) and proteins (B) in acute myeloid (THP-1) and lymphoid (Jurkat) leukaemia cell lines when treated with their lowest significant doses (LSDs) that induce apoptosis (determined previously in Mahbub et al., 2013, 2015, 2019) for 24 h. Gene and protein data are expressed as medians and ranges. Results were considered statistically significant when P ≤ 0.05 (*). The combination treatment effects and colours were determined based on the statistical analysis described in.
Figure 5
Figure 5
Effects of apigenin (AP) alone and in combination with etoposide (ETP) and cyclophosphamide (CYCLO) on expression of TRAILR1/DR4 and TNFR1/TNFRSF1A death receptors genes (A) and proteins (B) in acute myeloid (THP-1) and lymphoid (Jurkat) leukaemia cell lines when treated with their lowest significant doses (LSDs) that induce apoptosis (determined previously in Mahbub et al., 2013, 2015, 2019) for 24 h. Gene and protein data are expressed as medians and ranges. Results were considered statistically significant when P ≤0.05 (*). The combination treatment effects and colours were determined based on the statistical analysis as described in.
Figure 6
Figure 6
Effects of apigenin (AP) alone and in combination with etoposide (ETP) and cyclophosphamide (CYCLO) on expression of FAS/CD95 death receptor and FADD domain genes (A) and proteins (B) in acute myeloid (THP-1) and lymphoid (Jurkat) leukaemia cell lines when treated with their lowest significant doses (LSDs) that induce apoptosis (determined previously in Mahbub et al., 2013, 2015, 2019) for 24 h. Gene and protein data are expressed as medians and ranges. Results were considered statistically significant when P ≤ 0.05 (*). The combination treatment effects and colours were determined based on the statistical analysis as described in.
Figure 7
Figure 7
Effects of apigenin (AP) alone and in combination with etoposide (ETP) and cyclophosphamide (CYCLO) on expression of caspase genes (A) and proteins (B) in acute myeloid (THP-1) and lymphoid (Jurkat) leukaemia cell lines when treated with their lowest significant doses (LSDs) that induce apoptosis (determined previously in Mahbub et al. 2013, 2015, 2019) for 24 h. Gene and protein data are expressed as medians and ranges. Results were considered statistically significant when P ≤ 0.05 (*). The combination treatment effects and colours were determined based on the statistical analysis as described in.
Figure 8
Figure 8
A summary of the effects of apigenin and etoposide combination treatments on apoptosis-related gene and protein expression in acute leukaemia cells (Jurkat and THP-1).
Figure 9
Figure 9
A summary of the effects of apigenin and cyclophosphamide combination treatments on apoptosis-related gene and protein expression in acute leukaemia cells (Jurkat and THP-1).
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