Table 2.
Antitumor effects of TCM-combination therapy
| Monomer composition | Combination therapy | Cellular, animal levels | Advantages of combination therapies | Reference |
|---|---|---|---|---|
| Curcumin (Cur) | Cur + cisplatin | Human non-small-cell lung cancer (NSCLC) A549, A549-xenograft mouse model | Cur can strengthen the antitumor effect of cisplatin in A549 cells in vitro. Cur combined with cisplatin can inhibit tumor growth and promote apoptosis in xenograft mouse model. | 108 |
| Cur + paclitaxel | Breast cancer cell line MCF7, MCF7-xenograft mouse model | Cur combined with paclitaxel can inhibit the growth of MCF7 cells synergistically, induce significant apoptosis in MCF7 cell lines, and exert increased antitumor efficacy in mouse models. | 117 | |
| Cur + Rsv | Breast epithelial MCF10A-Tr, tumor xenograft in mice | Cur and Rsv causes apoptosis synergistically in breast cancer cells by p2 Waf/Cip1-mediated inhibition of Hedgehog–Gli cascade. | 109 | |
| Colon cancer HCT116 (wild type) cells, xenografts in SCID mice | The combination of Cur and Rsv has stronger inhibitory effects on the growth of p53-positive (wild type) and p53-negative (HCT116) colon cancer cells in vitro and in vivo than either agent alone. | 119 | ||
| Cur + Rsv–diallyl disulfide | Malignant rhabdoid (SJRH4, RD/18) and osteosarcoma (SAOS2) cell lines | Cur induces apoptosis in rhabdomyosarcoma and osteosarcoma cells, which is potentiated when Cur is combined with Rsv or diallyl disulfide. | 120 | |
| Cur + As2O3/lonidamine | U937 and HL60 human acute myeloid leukemia cells, K562 chronic myelogenous leukemia cells | Cur plus As2O3 or lonidamine stimulates events typical of the mitochondrial executioner pathway. Cotreatment with Cur may be an effective way to improve the efficacy of As2O3 and lonidamine as antineoplastic agents for myeloid leukemia cells. | 121 | |
| Cur + vesicular stomatitis virus | PC3 prostate cancer cells, mouse model of prostate cancer | Cur makes prostate cancer cells sensitive to the oncolytic effects of vesicular stomatitis virus through modulating antiviral responses and components of the intrinsic apoptotic pathway. | 122 | |
| Cur + Qct | Human gastric cancer MGC803 cells | The combination of Cur and Qct has a significant inhibitory effect on cell proliferation and a stronger effect on gastric cancer MGC803 cells than individual therapy. | 123 | |
| Arsenic trioxide (ATO) | ATO + artesunate | Human K562 cell lines | Artesunate combined with ATO can significantly promote apoptosis of K562 cells induced by artesunate. | 124 |
| ATO + dihydroartemisinin | A549 cells | Dihydroartemisinin effectively sensitizes A549 cells to ATO, increasing the effectiveness of ATO-induced cell death, and can cooperate with ATO to exert synergistic effects in promoting apoptosis in A549 lung cancer cells. | 85 | |
| ATO + cisplatin– doxorubicin (Dox) | HepG2 cell lines, hepatic cancer stem cells | This study was critical in realizing the potential for synergy between ATO and chemotherapeutic protocols, such as cisplatin and Dox. | 125 | |
| Human hepatoma BEL7402 cells, mouse hepatoma HepA | Low-dose cisplatin or Dox and ATO in combination can increase the antihepatocarcinoma effect. | 126 | ||
| ATO + Dox | SGC7901/S human GC cell line, Dox-resistant SGC7901/ADM cell line | ATO can reverse MDR to Dox in human GC cells. This may be relevant to decreased Pgp expression. | 127 | |
| ATO + matrine | Myeloma cell lines RPMI 8226 and U266 | Matrine shows an antimyeloma effect by inducing apoptosis, and ATO combined with matrine enhances apoptosis induced by matrine, having synergistic effects. | 128 | |
| Resveratrol (Rsv) | Rsv + cisplatin | A549 cells | Rsv combined with cisplatin synergistically induced apoptosis by modulating autophagic cell death in A549 cells. | 104 |
| Rsv + Dox | MCF7 and MDA-MB231 cell lines, Ehrlich ascitic carcinoma–bearing mice | Rsv combined with Dox can inhibit tumor volume and prolong the life of Ehrlich ascitic carcinoma cell–bearing mice. | 129 | |
| Rsv + paclitaxel | HepG2 human liver cancer cells | Rsv can enhance the anticancer effect of paclitaxel on HepG2 cells and be used as a sensitizer of paclitaxel. | 130 | |
| NSCLC cell line A549 | Rsv enhances the anticancer effects of paclitaxel in A549 cells, and thus Rsv might be used as an excellent sensitizer for paclitaxel. | 131 | ||
| Rsv + temozolomide | Human glioblastoma U87 MG and GBM8401 cell lines, GBM-SKH (GBM) cell line, orthotopic xenograft model | Rsv can enhance temozolomide-mediated antitumor effects in glioblastoma multiforme in vitro and in vivo by ROS-dependent AMPK–TSC–mTOR signaling pathway. | 132 | |
| Rsv + Qct | Human hepatoblastoma HepG2 cells | Rsv plays different roles in autophagy according to cellular energy state, and can represent a promising strategy to sensitize cancer cells to Qct therapy. | 133 | |
| Rsv + As2O3 | HeLa, MCF7, and NB4 cells, HeLa-cell mouse model | Rsv can significantly raise the antitumor effect induced by As2O3 in vitro, and As2O3 combined with Rsv can significantly inhibit tumor growth and angiogenesis in nude mice. | 134 | |
| Ginsenoside Rg3 | Rg3 + As2O3 | NCIH1299 lung cancer cells, nude mice bearing hepatoma | As2O3 combined with Rg3 can dramatically inhibit proliferation of NCIH1299 cells and prolong the survival of nude mice bearing tumors, having a significant effect on lung cancer therapy. | 112 |
| Rg3 + paclitaxel | Triple-negative breast cancer lines MDA-MB231, sMDA-MB453, BT549, mouse MDA-MB231-xenograft model | Rg3 promotes cytotoxicity and apoptotic effects of paclitaxel on triple-negative breast cancer through inhibition of NFκB activity and regulating Bax/Bcl2 expression. | 113 | |
| Rg3 + paclitaxel/cisplatin | Mouse tumor-xenograft models | The combined use of Rg3 can remarkably raise the inhibitory effects of chemotherapy on tumor growth, and expression levels of Ki67 in the chemotherapy + Rg3 group were significantly lower than in the other groups (Rg3 alone, paclitaxel alone, and cisplatin alone). | 114 | |
| Rg3 + docetaxel | Colon cancer (HCT116 and SW620) cells | Compared to treatment with Rg3 or docetaxel alone, combination therapy can inhibit the growth of cancer cells and induce apoptosis of cancer cells more effectively, accompanied by significant inhibition of NFκB activity. | 135 | |
| Baicalein (BA) | BA + taxol | Human ovarian cancer A2780 cells, SKOV3 cells, and OVCAR cells | BA combined with taxol at low concentrations can play a synergistic antitumor role via the Akt–β-catenin signaling pathway and mitochondria-mediated cell apoptosis in ovarian cancer cells. | 136 |
| BA + 10-hydroxycamptothecin (Hcpt) | BGC823, MCF7, and SMMC7721 cells, mice xenografted with BGC823 tumors | In BGC823, MCF7, and SMMC7721 cells, BA significantly enhances the anticancer activity of Hcpt at an atoxic dose. Hcpt with BA is a novel and effective combination therapy, which synergistically target Topo I and upregulate p53 to induce cell-cycle arrest and cell apoptosis. | 115 | |
| Gambogic acid (GA) | GA + cisplatin | Human NSCLC A549, NCIH460, and NCIH1299 cell lines | GA synergizes the growth-inhibitory activity of CDDP and enhances the apoptosis-induced effect of CDDP on NSCLC cells, meanwhile sensitizing lung cancer cells to CDDP in vitro and in vivo. | 137 |
| GA + gemcitabine | PANC1 and BxPC3 cells, mouse xenograft model of human pancreatic cancer | GA inhibits the activation of ERK–E2F1–RRM2 signaling pathway to sensitize pancreatic cancer cells to gemcitabine in vitro and in vivo. | 138 | |
| GA + sunitinib | Renal carcinoma cell lines 786O and CAKI1, mouse xenograft models | Therapy of 786O and CAKI1 cells with GA or sunitinib can reduce the proliferation of tumor cells, especially when combined with the two medicines. The combination of GA and sunitinib has greater antitumor efficacy than either drug alone. | 139 | |
| Gambogenic acid (GNA) | GNA + adriamycin (Adr) | MCF7 cell lines, MCF7/ADR cell lines | GNA can increase the chemosensitivity of breast cancer cells to Adr. This modulatory role is mediated by suppression of the PTEN–PI3K–Akt pathway, leading to apoptosis in MCF7/ADR cells. | 140 |
| GNA + bortezomib (Btz) | Myeloma MM1S cells, tumor-xenograft models | Btz and GNA have strong synergistic effect in combination therapy, inducing apoptosis of MM.1S cells. The combination of Btz and GNA is superior to single drug on MM.1S-xenograft models. | 141 | |
| Quercetin (Qct) | Qct + tamoxifen | Prostate-tumor xenografts in mice | Tamoxifen combined with Qct can effectively delay the occurrence of tumors, inhibit the final volume of tumors, and reduce the weight of the end-point tumor (P<0.05). | 142 |
| Qct + metformin | PC3 and LNCaP cells, prostate cancer xenografts in nude mice | Combined application of metformin and Qct has a significantly stronger effect on apoptosis of prostate cancer cells than monotherapy, and combination therapy can inhibit the VEGF–Akt–PI3K signaling pathway to play a synergistic antitumor effect. | 143 | |
| Qct + trichostatin A | Mouse xenograft model of A549 cells | Qct enhances the antitumor effect of trichostatin A and prevents trichostatin A-induced muscle wasting. | 144 | |
| Qct + Hcpt | MCF7, BGC823, and HepG2 cells, MCF7 xenograft in nude mice | The combination of Qct and Hcpt can inhibit Topo I in MCF7 cells, which synergistically induces cell-cycle arrest and apoptosis by triggering DNA damage. | 145 | |
| Qct + irinotecan–SN38 | The AGS human gastric adenocarcinoma cell line, AGS xenograft mouse model | Qct combined with irinotecan has a superior regulatory effect on angiogenesis and EMT-related factors. Qct may enhance the efficacy of irinotecan–SN38 in the human AGS cell line. | 146 | |
| Triptolide (TL) | TL + sorafenib | Huh7 and PLC/PRF/5 cells, Huh7 tumor-xenograft mouse model | Sorafenib combined with TL is superior to single-drug therapy in increasing cell death and apoptosis in vitro. | 147 |
| TL + cisplatin | Human gastric adenocarcinoma SCM1 cells, xenografts in SCID mice | TL can raise the cytotoxicity of cisplatin to SCM1 cells, and the combined therapy can significantly inhibit the growth of tumors. | 111 | |
| Urothelial cancer cells, PC3 prostate cancer cell line, mouse xenograft model | Cancer-specific enhancement of cisplatin-induced cytotoxicity with TL by the interaction of inactivated GSK3β with p53. | 148 | ||
| TL + oxaliplatin | Colon cancer cell line SW480, nude mouse model | Combination therapy with TL and oxaliplatin exerts synergistic antitumor effects at low concentrations in colon cancer cells, with less cytotoxicity, which exhibits high potency for clinical applications. | 149 | |
| TL + fluorouracil | Colon carcinoma HT29 cells, tumor xenografts in nude mice | The combined effects of TL and fluorouracil on the growth of colon carcinoma are better than that of single drug, whether in vitro or in vivo. TL combined with fluorouracil has synergistic effects at lower concentrations and promotes apoptosis, but the side effects of chemotherapy are not increased. | 150 | |
| TL + gemcitabine | Pancreatic cancer BxPC3 and PANC1 cell lines | TL can increase gemcitabine-induced cell-growth inhibition and apoptosis synergistically. When TL is combined with gemcitabine, the potential for therapy of pancreatic cancer increases markedly. | 151 | |
| Berberine (Bbr) | Bbr + Dox | Human breast cancer MCF7/MDR cells, tumor xenografts in the BALB/c nu/nu mice | Bbr can increase the sensitivity of drug-resistant breast cancer to Dox chemotherapy and can directly induce apoptosis in vitro and in vivo by dose-orchestrated AMPK signaling. | 152 |
| NSCLC NCIH460, NCIH1975 cells | Bbr inhibits Dox-mediated STAT3 activation and enhances the cytotoxic effect in lung cancer cells of Dox treatment. | 153 | ||
| Bbr + evodiamine | Human breast cancer MCF7 cells, mice with MCF7 human breast cancer xenografts | Bbr combined with evodiamine plays a synergistic role in inhibiting the proliferation of MCF7 cells through inducing cell-cycle arrest and apoptosis. | 154 | |
| Bbr + galangin | ECA9706 cells, nude mice with xenograft tumors | Galangin combined with Bbr synergistically exerts cell-growth inhibition, apoptosis, and cell-cycle arrest in esophageal carcinoma cells and also exhibits outstanding synergistic anticancer role in vivo. | 155 | |
| Bbr + tamoxifen | MCF7 and MCF7/TAM cells | Bbr combined with tamoxifen is more effective than tamoxifen alone in inducing cell-growth inhibition, inducing G1-phase arrest and activating cell apoptosis. | 156 | |
| Bbr + sorafenib | SMMC7721 and HepG2 cells | The combination of Bbr and sorafenib exhibits a synergistic inhibitory effect on the proliferation of SMMC7721 and HepG2 cells. | 157 | |
| Allicin (AN) | AN + IL2 | BXPC3 cell line, pancreatic cancer xenograft in mice | The combination of AN and IL2 can inhibit the growth of tumors and prolong survival, possibly by activation of CD4+ T, CD8+ T, and NK cells. | 158 |
| AN + fluorouracil | SK-Hep1 and BEL7402 cell lines, hepatocellular carcinoma-xenograft models in nude mice | By ROS-mediated mitochondrial pathway, AN can increase the sensitivity of hepatocellular carcinoma cells to fluorouracil-induced-apoptosis. Combination of AN and fluorouracil can be used as a novel chemotherapeutic regimen for hepatocellular carcinoma. | 159 | |
| Dihydroberberine (Dhb) | Dhb + sunitinib | Human NSCLC NCIH460, NCIH460 cell-xenografted nude mice | Sunitinib shows synergistic effects on proliferation, colony formation, and growth of transplantable tumors of NCIH460 cells, suggesting that Dhb can increase the sensitivity of lung cancer to sunitinib. | 160 |
| Oxymatrine (Omt) | Omt + oxaliplatin | Colon cancer lines (HT29 and SW480), SW480 xenograft mouse model | A combined index value <1 for Omt and oxaliplatin has a synergistic effect. Compared with oxaliplatin or Omt alone, combination therapy has more effective inhibition on tumor weight and volume of SW480-xenotransplant mice. | 161 |
| Omt + NM3 | Human gastric cancer cell lines SGC7901, MKN45, MKN74, human gastric cancer xenografted in mice | Omt combined with NM3 can synergistically inhibit the growth of human gastric cancer cell line SGC7901 in vitro and the growth of xenograft human gastric cancer cell line SGC7901 in vivo. | 162 | |
| Tetraarsenic oxide (TAO) | TAO + cisplatin | Human cervical carcinoma cell line HPV16, CaSki cells, mice bearing CaSki-cell tumors | TAO can induce apoptosis. Combined with cisplatin, it can significantly increase the number of apoptotic cells, exerting a synergistic role. | 163 |
| Cryptotanshinone (Cts) | Cts + cisplatin | A549 cells, A549/DDP cells | Compared with cisplatin monotherapy, the combination of Cts and cisplatin induces cell death and apoptosis by increasing the sensitivity of A549/DDP cells to cisplatin. Cts can reverse the resistance of human lung cancer A549 cells to cisplatin by downregulating the Nrf2 pathway. | 110 |
| Tetramethylpyrazine (Tmp) | Tmp + cisplatin (CDDP) | Lewis lung cancer mice | The inhibitory effect of Tmp combined with DDP on tumor growth is enhanced compared to Tmp- or CDDP-alone treatment. Tmp with CDDP had additional or synergistic effects to inhibit tumor growth effectively. | 164 |
| Catechin (RQC) | RQC + gefitinib | Human metastatic breast cancer cell line MDA-MB231, hairless SCID female mice | Combination of RQC and gefitinib can significantly reduce the viability of gefitinib- resistant breast cancer cells. Compared with RQC or gefitinib alone, it can significantly inhibit the growth and metastasis of breast tumors in nude mice. | 165 |
| Dihydroartemisinin (Dha) | Dha + gemcitabine | BxPC3 and PANC1 cell lines, BALB/c nude mice | Dha significantly enhances the inhibition and apoptosis of gemcitabine on BxPC3 and PANC1 cell lines in vitro. Combination therapy can significantly enhance the antitumor effect of gemcitabine. | 80 |
| Epigallocatechin- 3-gallate (EGCG) | EGCG + Dox | Human prostate-cell lines, mouse tumor modeling with PC3ML cells | EGCG can be effectively used to improve the efficacy of Adr through improving its ability to eradicate highly aggressive, metastatic, or primary tumors. | 166 |
| Human HCC cell line BEL7404/Dox, xenograft mouse model | EGCG can enhance Dox-induced cytotoxicity and increase the sensitivity of drug-resistant hepatocellular carcinoma cells to Dox at an atoxic dose. | 167 | ||
| Ginsenoside Rh2 | Rh2 + paclitaxel–mitoxantrone | LNCaP prostate-tumor cells, human LNCaP-tumor xenograft | Rh2 combined with paclitaxel shows stronger inhibition and synergistic effect on growth in a cultured LNCaP cell line. | 88 |
Abbreviations: SCID, severe combined immunodeficiency; MDR, multidrug resistance; CDDP, cis-diamminedichloroplatinum; EMT, epithelial–mesenchymal transition.