Table 2.

Combination experimental design of natural compounds with conventional anticancer therapy and the outcomes of these studies.

Natural Compound	Combination Therapy	Concentration Used	Type of Cancer	Outcomes of the Combination	Intersecting Mechanism	References
Curcumin	Curcumin/Paclitaxel	Curcumin 5 µM Taxol 5 nM	Cervical cancer	Curcumin enhanced paclitaxel-induced apoptosis by increasing p53 expression, activation of caspase-3, 7, 8, and 9, cleavage of poly(ADP-ribose) polymerase (PARP), and cytochrome c release	Non intersecting Curcumin enhanced paclitaxel-induced apoptosis by down-regulation of Nuclear Factor-κB and the Serine/Threonine Kinase Akt	[35,36]
	Curcumin/Docetaxel	Curcumin 20 μM Docetaxel 10 nM	Prostate cancer	Reduced docetaxel-induced drug resistance and side effects	Non intersecting curcumin enhances the efficacy of docetaxel treatment by inhibiting proliferation and inducing apoptosis through modulation of tumor-suppressor proteins, transcription factors and oncogenic protein kinases compared to each treatment alone	[38]
	Curcumin/Metformin	Curcumin 5–40 μM Metformin 0.4–12 mM	Prostate cancer	Synergistic impact on growth inhibition by apoptotic induction than curcumin and metformin alone	Apoptosis	[40]
	Curcumin/5-FU	curcumin 5 µM 5-FU 0.1 µM	Colorectal cancer	Overcome the drug resistance caused by 5-FU	Non-intersecting Curcumin decreases cancer stem cells and making cancer cells more sensitive to 5-FU	[42]
	Curcumin/Celecoxib	Curcumin 10–15 μmol/L Celecoxib 5 μmol/L	Colorectal cancer	Inhibited cancer cell proliferation	Growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Curcumin augmented celecoxib inhibition of prostaglandin E2 synthesis. The drugs synergistically down-regulated COX-2 mRNA expression.	[43]
	Curcumin/Cisplatin	Curcumin 10 M Cisplatin 10 M	Bladder cancer	Stimulated caspase-3 and overexpression phospho-mitogen-activated protein kinase (p-MEK) and phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) signaling	activating caspase-3 and upregulating phospho-mitogen-activated protein kinase (p-MEK) and phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) signaling	[44]
	Curcumin/Doxorubicin	Curcumin 5 M Doxorubicin 0.4 mg/mL	Hodgkin lymphoma	Reduced cell growth by 79%	reduced cell growth by 79%, whereas each drug alone reduced L540 cell growth by 44% and 23%	[45]
Resveratrol	Resveratrol/Temozolomide	Resveratrol 12.5 mg/kg Temozolomide 10 mg/kg TMZ	Malignant glioma	Enhanced temozolomide’s therapeutic efficacy by inhibiting ROS/ERK-mediated autophagy and improving apoptosis	reduced tumor volumes by suppressing ROS/ERK-mediated autophagy and subsequently inducing apoptosis protected glioma cells from apoptosis, thus improving the efficacy of chemotherapy for brain tumors.	[78]
	Resveratrol/Doxorubicin	Resveratrol 25 µM Resveratrol 10–100 µM Resveratrol 12.5 mg/kg	Melanoma	Induced cell cycle disruption and apoptosis, resulting in decreased melanoma growth and increased mouse survival	Non intersecting resveratrol inhibits the growth of a doxorubicin-resistant B16 melanoma cell subline (B16/DOX) induced G1-phase arrest followed by the induction of apoptosis reduced the growth of an established B16/DOX melanoma and prolonged survival (32% compared to untreated mice).	[79]
Genistein	Genistein/5-FU	genistein 1.3 mg/day intraperitoneally FU 60 mg/kg, intraperitoneally	Pancreatic cancer	Tumor cells were augmented by the addition of genistein, which increased both apoptosis and autophagy	Non intersecting Genistein can potentiate the antitumor effect of 5-FU by inducing apoptotic as well as autophagic cell death.	[99]
	Genistein/Photofrin	genistein (0, 50, 100 μM) Photofrin (0–50 μg/mL)	Ovarian cancer Thyroid cancer	Enhanced the efficacy of photofrin-mediated photodynamic therapy	Non intersecting genistein sensitizes the activity of photodynamic therapy by photofrin in SK-OV-3 cells by inducing apoptosis through the activation of caspase-8 and caspase-3	[51]
	Genistein/Estradiol	Genistein 20 μM Estradiol 20 μM	Human liver cancer	Enhanced apoptosis	Enhanced apoptosis	[98]
EGCG	EGCG/5-FU	EGCG 50 μM 5-FU 10 μM	Colorectal cancer	Improved tumor cell’s sensitivity to 5-FU through inhibition of 78-kDa glucose-regulated protein (GRP78), NF-KB, miR-155-p5 and multidrug resistance mutation 1 (MDR1) pathways	Non intersecting EGCG enhanced the chemo-sensitivity of 5-FU in low doses by inhibiting cancer proliferation, promoting apoptosis and DNA damage EGCG blocked GRP78 expression, followed by enhancement of NF-κBand miR-155–5p level, which further inhibited the MDR1 expression and promoted the 5-FU accumulation in tumor cell	[87]
	EGCG/Cisplatin	EGCG 10 μM Cisplatin 10 μM	Ovarian cancer	Enhanced cisplatin sensitivity in ovarian cancer by regulating the expression of copper and cisplatin influx transport which is well-known as copper transporter 1 (CTR1)	DNA damage	[125]
	EGCG/Tamoxifen	EGCG 25 mg kg−1 Tamoxifen 75 μg kg−1	Breast cancer	Decreased the expression of EGFR, mTOR, and CYP1B	Decreased the expression of EGFR, mTOR, and CYP1B	[126]
	EGCG/Paclitaxel	EGCG 20 μM Paclitaxel 1 μM	Breast cancer	EGCG had synergistically encouraged the effect of paclitaxel by enhancing the phosphorylation of c-Jun N-terminal kinase (JNK)	induced 4T1 cells apoptosis	[127]
	EGCG/Gefitinib	EGCG 20 μM Gefitinib 1.25 μM	Non-small cell lung cancer	Inhibition of epithelial-Mesenchymal transition (EMT), and blocking of mTOR pathway	inhibit proliferation of HCC827-Gef cells	[128]
	EGCG/Erlotinib	EGCG 30 μM Erlotinib 1 μM	Head and neck cancer	enhanced apoptosis through the regulation of Bcl-2-like protein11(BIM) and B-cell lymphoma 2(Bcl-2)	inhibiting the phosphorylation of ERK and AKT and expression induces apoptosis of SCCHN cells by regulating Bim and Bcl-2 at the posttranscriptional level.	[129]
Allicin	Allicin/Cisplatin	Allicin 10 μg/mL Cisplatin 2 μg/mL	Lung cancer	Allicin overcome hypoxia mediated cisplatin resistance by increasing ROS production	shifts the mechanism of cell death towards more apoptosis allicin induced increase in ROS accumulation thus enhances cisplatin sensitivity even at low doses in A549 cells.	[144]
	Allicin/5-FU	Allicin 5 mg/kg/d; every two days for 3 weeks 5-FU 20 mg/kg/d 5 consecutive days	Hepatic cancer	Improved its sensitivity in hepatic cancer cells due to induction of apoptosis by ROS-mediated mitochondrial pathways	increased intracellular reactive oxygen species (ROS) level, reduced mitochondrial membrane potential (ΔΨm), activated caspase-3 and PARP, and down-regulated Bcl-2	[154]
	Allicin/Adriamycin	Allicin 25 μg/mL Adriamycin 2.5 μg/mL	Gastric cancer	Inhibited the proliferation and induced apoptosis	induced apoptosis and inhibited proliferation	[148]
	Allicin/Tamoxifen	Allicin 10 nM Tamoxifen 1 μM	Breast cancer	Improved the effectiveness of tamoxifen	Non intersecting Allicin in MCF-7 cells enhances the effectiveness of tamoxifen in the presence and absence of 17-b estradiol	[149]
Thymoquinone	Thymoquinone/Doxorubicin	For most experiments Thymoquinone 10 µM TQ Doxorubicin 50 nM for 24 h for the treatment of HuT102 cells for 48 h Thymoquinone 40 µM Doxorubicin 100 nM	Adult T-cell leukemia	Increased ROS production resulting in disruption of the mitochondrial membrane	Increased ROS production resulting in disruption of the mitochondrial membrane inhibition of cell viability and increased sub-G1 cells reduced tumor volume	[169]
	Thymoquinone/Cisplatin	Thymoquinone 20 mg·kg−1 oral cisplatin 2 mg·kg−1 ip	Hepatocellular carcinoma	Improved the effectiveness of Cisplatin via controlling the GRP78/CHOP/caspase-3 pathway	reduced the elevated GRP78 and induced CHOP-mediated apoptosis in the diseased liver tissues normalized alpha-fetoprotein (AFP) levels and improved liver functions	[167]
	Thymoquinone/Cisplatin/Pentoxifyllin	Thymoquinone i.p. (20 mg/kg) Cisplatin 7.5 mg/kg twice Pentoxifyllin s.c. route 15 mg/kg	Breast carcinoma	Enhance the effect of the treatment by Notch pathway suppression	reduced Notch1, Hes1, Jagged1, β-catenin, TNF-α, IL-6, IFN-γ, and VEGF with increment in IL-2, CD4, CD8, and apoptotic cells Notch suppression.	[170]
	Thymoquinone/Paclitaxel	100:1 μM of TQ with PTX	Breast cancer	increased the rate of apoptotic/necrotic cell death	Non intersecting Thymoquinone does not improve Paclitaxel potency against MCF-7 or T47D cells and apparently antagonizes its killing effects. However, TQ significantly abolishes tumor-associated resistant cell clones Thymoquinone enhanced Paclitaxel induced cell death including autophagy TQ significantly increased the percent of apoptotic/necrotic cell death in T47D cells after combination with paclitaxel induced a significant increase in the S-phase cell population	[168]
Piperine	Piperine/Paclitaxel	5:1	Breast cancer	Synergistic anticancer effect	Non intersecting piperine can improve the bioavailability of paclitaxel and can potentiate the antitumor effect of paclitaxel	[189]
	Piperine/hesperidin/bee venom/Tamoxifen	Piperine 34.89 μg/mL Hesperidin 12.14 μg/mL bee venom 10.19 μg/mL Tamoxifen 2.98 μg/mL	Breast cancer	Enhance the anti-cancer effects of tamoxifen	Enhance the anti-cancer effects of tamoxifen	[190]
	Piperine/Doxorubicin	Piperine 50 µM Doxorubicin 10 µM	Breast cancer	Inhibited tumor growth	Piperine enhanced the cytotoxicity effect of doxorubicin	[191]
	Piperine/Docetaxel	Piperine 50 mg/kg p.o. Docetaxel 12.5 mg/kg	Prostate cancer	Improved the antitumor efficacy of docetaxel	Improved Anti-Tumor Efficacy Via Inhibition of CYP3A4 Activity	[192]
Emodin	Emodin/Sorafenib	Emodin 20 μM Sorafenib 0.5 μM and 1 μM	Hepatocellular carcinoma	Improving the anti-cancer effect of sorafenib by increasing apoptosis and cell cycle arrest	Non intersecting emodin synergistically increased cell cycle arrest in the G1 phase and apoptotic cells in the presence of sorafenib	[207]
	Emodin/Afatinib	Emodin 50 mg/kg/day for 4 weeks Afatinib 50 mg/kg/day for 4 weeks;	Pancreatic cancer	Inhibited cell proliferation	Regulating the Stat3 expression.	[216]
	Emodin/Cisplatin	Emodin A549 cells:5 µM H460 cells, 2.5 µM Cisplatin A549: 8, 10 and 15 µM H460 cells:2, 4, 6, 8 and 10 µM	Lung adenocarcinoma	Increased cisplatin sensitivity through P-glycoprotein downregulation	Non intersecting Emodin inhibited the proliferation of A549 and H460 cells emodin enhanced cisplatin-induced apoptosis and DNA damage in A549 and H460 cells emodin can increase A549 and H460 cell sensitivity to cisplatin by inhibiting Pgp expression	[219]
	Emodin/Paclitaxel	Emodin 10 μM Paclitaxel 4 μM	Non-small cell lung cancer	Enhanced the antiproliferative effect of paclitaxel	Inhibited the proliferation of A549 cells	[212]
	Emodin/Gemcitabin	Emodin 40 μM Gemcitabine 20 μM	Pancreatic cancer	Emodin inhibited IKKβ/NF-κB signaling pathway and reverses Gemcitabine resistance	Increase the apoptosis rate	[213]
	Emodin/Endoxifen	Emodin 0, 15, 30, 60 µM Endoxifen 0, 2, 4 µM	Breast cancer	Elevation of cyclin D1 and phosphorylated extracellular signal-regulated kinase (pERK)	Emodin attenuated tamoxifen’s treatment effect via cyclin D1 and pERK up-regulation in ER-positive breast cancer cell lines.	[294,299]
Parthenolide	Parthenolide/Epirubicin	Parthenolide 2.5, 0.75 and 0.2 µM Epirubicin (9, 7, and 5 µM	Breast cancer	improved cytotoxicity and apoptosis as well as reduced the undesirable side effects	Up-regulated the expression of Bax as a pro-apoptotic gene in MDA-MB cells down-regulated the expression of Bcl2 as an anti-apoptotic gene in MDA-MB cells increasing the fracture of caspase 3 and improving the apoptosis pathway	[221]
	Parthenolide/Indocyanine		Breast cancer	Synergistic antitumor activity	More ROS-mediated killing of the tumor cells by exerting a synergistic effect for treating triple-negative breast cancer	[270]
	Parthenolide/Arsenic trioxide	Parthenolide 1 μg/mL Arsenic trioxide 2 µM	Adult T-cell leukemia/lymphoma	Enhanced the activity	Non intersecting parthenolide significantly enhanced the toxicity of ATO in MT2 cells.	[231]
	Parthenolide/Balsalazide	Parthenolide 5 and 10 μmol/L Balsalazide 20 mmol/L	Colorectal cancer	Improved the anticancer activity via blocking NF-κB activation	Exhibits synergistic suppression of NF-κB and NF-κB–regulated gene products that are associated with apoptosis, proliferation, invasion, angiogenesis, and inflammation	[232]
Luteolin	Luteolin/Cisplatin	Luteolin 0, 10, 50, 100 μM Cisplatin 2 μg/mL	Ovarian cancer	Significantly sensitized the antineoplastic effect of cisplatin by initiating apoptosis and inhibiting cell invasion and migration	Suppressing CAOV3/DDP cell growth and metastasis inducing apoptosis by decreasing Bcl-2 expression.	[245]
	Luteolin/5-FU	Luteolin:5-fluorouracil 10:1, 20:1, 40:1 luteolin:100, 50, 25, 12.5, 6.25, 3.125 µM 5-FU: 10, 5, 2.5, 1.25, 0.5, 0.25 µg/mL	Hepatocellular carcinoma	synergistic anticancer effect	Apoptosis induction and metabolism	[244]
Quercetin	Quercetin/Cisplatin	Quercetin 100 μM cisplatin 5 μg/mL	Oral squamous cell carcinoma	Inhibition of NF-κB thus downregulating of X-linked inhibitor of apoptosis protein(xIAP)	Induced apoptosis in human OSCC (cell lines Tca-8113 and SCC-15) by down-regulating NF-κB	[273]
		Quercetin 50 μM cisplatin 10 μM	Hepatocellular carcinoma	potentiated the growth suppression effect of cisplatin	Inducing growth suppression and apoptosis in HepG2 cells	[268]
		quercetin 15 μM cisplatin 10 μM	Cervical cancer	Induced apoptosis by downregulation of MMP2, METTL3, P-Gp and ezrin production	Promoting apoptosis and inhibiting proliferation, migration and invasion of cervical cancer cells	[262]
	Quercetin/Tamoxifen	Quercetin 50 μM Tamoxifen 10–6 mol/L	Breast cancer	Enhanced the activity	Proliferation inhibition and apoptosis in MCF-7Ca/TAM-R cells	[264]
	Quercetin/Vincristine	Vincristine 50 mg Quercetin 50 mg	Lymphoma	Potentiated the effect of vincristine	Synergistic effect through lipid-polymeric nanocarriers (LPNs) for the lymphoma combination chemotherapy	[269]
	Quercetin/Doxorubicin	Quercetin 0.7 μM Doxorubicin 2 μg/mL	Breast cancer	Suppression of efflux receptors (BCRP, P-gp, MRP1), and reduced the side effects of doxorubicin	Down-regulating the expression of efflux ABC transporters including P-gp, BCRP and MRP1 and attenuating the toxic side effects of high dose doxorubicin to non-tumor cells	[265]
		Quercetin and Doxorubicin 5 mg/kg	Gastric cancer	Improved the efficacy	Improved the efficacy of gastric carcinoma chemotherapy	[267]
		Doxorubicin 0.75 μM Quercetin 230 μM	Breast cancer	Improved the efficacy	Induction of apoptosis in cancer cells	[266]
	Quercetin/Radiotherapy	Theranostic system (CQM ) 50 μm	Breast cancer	Improved the tumor targeting and radiotherapy treatment	Promoted tumor cell apoptosis	[272]
	Quercetin/Paclitaxel	Quercetin 20 µM Paclitaxel 5 nM	Prostate cancer	Improved efficacy by by ROS production, induction of apoptosis, preventing cell migration and causing cell arrest in G2/M phase	Induction of apoptosis cell arrest in G2/M phase ROS production Preventing cell migration	[270]
		Quercetin 2, 10, 20 mg/kg Paclitaxel 40 mg/kg	Breast cancer	had enhanced the multi-drug resistance in breast cancer by decreasing P-gp expression	Lower IC50 value, higher apoptosis rate, obvious G2M phase arrest as well as stronger microtubule destruction in MCF-7/ADR cells	[271]
Anthocyanins	Anthocyanins/ 5-FU	Caco2 cells BRB Anthocyanins 50 μg/mL 5-FU 25 μM or 50 μM SW480 cells BRB Anthocyanins 50 μg/mL 5-FU 16 μM or 32 μM	Colorectal cancer	decreased the proliferation and migration of tumor cells	Decreased number of tumors decreased the proliferation	[287]
	Anthocyanins/Cisplatin	AIMs Anthocyanins 400 µg/mL Cisplatin 5 μg/mL	Breast cancer	advanced the sensitivity of cisplatin by inhibiting Akt and NF-κB activity	Non intersecting Anthocyanins isolated from Vitis coignetiae Pulliat (Meoru in Korea) (AIMs) Enhances Cisplatin Sensitivity in MCF-7 Human Breast Cancer Cells through Inhibition of Akt and NF-κB Activation	[289]
	Anthocyanins/Doxorubicin	Anthocyanins 1–25 μg/mL Doxorubicin 5 μM	Breast cancer	decreased doxorubicin cardiac toxicity	Smoothies containing mixtures of Citrus sinensis and Vitis vinifera L. cv. Aglianico N, two typical fruits of the Mediterranean diet decreased doxorubicin cardiac toxicity	[291]
	Anthocyanins/Trastuzumab	C3G 5 μg/mL Trastuzumab 5 μg/mL	Breast cancer	Improved trastuzumab apoptotic effect	Non intersecting Improved trastuzumab apoptotic effect	[294]
		C3G (1 mg/mL) or P3G (1 mg/mL)	Breast cancer	Overcome trastuzumab-resistant cells due to the decrease in HER2, AKT and MAPK activities	Non intersecting Anthocyanin overcome trastuzumab-resistant cells due to the decrease in HER2, AKT and MAPK activities inhibits invasion and migration of trastuzumab-resistant human breast cancer cells	[295]