Table 3.

Synergetic effect of CA in cancer cells.

Aim	Cancer Type: Model	Treatment Conditions	Finding	Reference
To assess the efficacy of cisplatin + CA treatment in human cervical cancer	• In vitro: human cervical cancer cell lines: HeLa, SiHa, CaSki (HPV-positive), and C33A (HPV- negative) cells.	CA (300 µM) and cisplatin (11 µM) for 24 h	The combination of cisplatin and CA significantly inhibited cell growth of HeLa and CaSki cell lines, with a combination index < 1, indicating a synergistic effect. The combination significantly increased the expression of caspases 3, 7, and 9, demonstrating apoptosis.	[128]
To assess the efficacy of the combined treatment with cisplatin + CA against ovarian carcinoma	• In vitro: ovarian carcinoma cells A2780 and ovarian carcinoma- resistant A2780cisR cells.	CA (10 µM) and cisplatin (5 µM) for 24 h	The combined therapy restores the sensitivity of resistant cells to cisplatin, achieving a similar level of cell viability as that observed in sensitive cells (60% viability). When the cisplatin/caffeic acid ratio was increased to 1:10 (5:50 µM), the caspase activity rose significantly by 4.3-fold.	[130]
To evaluate the effects of metformin (Met) and CA on metastatic human cervical cancer	• In vitro: metastatic human cervical HTB-34 cell line.	CA (100 µM) and Met (10 mM) for 24 h	CA (100 µM) and Met (10 mM) activated AMPK. CA increased oxidative stress, affecting bioenergetics pathways and making HTB-34 cells more sensitive to Met. CA and Met suppressed HTB-34 cells by different mechanisms.	[133]
To determine the efficacy and underlying mechanisms of CA in combination with paclitaxel for the treatment in human non-small cell lung carcinoma (NSCLC)	• In vitro: human non-small cell lung carcinoma H1299 cells. • In vivo: mouse xenograft model by subcutaneous injections of H1299 cells.	In vitro: 100 μM CA + 10 μM of paclitaxel for 24 h In vivo: 20 mg/kg CA and 10 mg/kg paclitaxelad ministered concomitantly for three weeks.	In vitro, combination treatment decreased the proliferation of NSCLC H1299 cells by the MAPK pathway. CA induced sub-G1 cell cycle arrest in H1299 cells. In vivo, the combined treatment with CA and paclitaxel exerted a more effective suppressive effect on tumor growth in H1299 xenografts without causing significant adverse effects.	[134]
To evaluate the synergistic antitumor activity and the physicochemical and pharmacokinetic properties of caffeic acid/5-FU-cocrystal in vitro and in vivo.	• In vitro: human colon cancer HCT-116, breast cancer MDA-MB-231, and lung cancer A549 cell lines • In vivo: Sprague Dawley rats	In vitro: HCT-116; MDA-MB-231 (15.19 μM); and A549 (11.57 μM) of caffeic acid/5-FU cocrystal for 48 h. In vivo: oral dose of 50 mg kg−1.	In vitro: Cocrystallization of CA + 5-FU optimized the physicochemical properties of 5-FU and exerted a synergistic antitumor effect (CI < 1), thus enhancing the anticancer activity of 5-FU. In vivo: The aqueous solubility and permeability of 5-FU in the cocrystal increased by 1.92 and 4.22-fold, respectively, compared to the original drug 5-FU.	[131]
To evaluate the effects of CA and imatinib (IM) and their synergistic effects on chronic myeloid leukemia model	• In vitro: human myelogenous leukemia cell line K562 and (IM)-resistant cells.	Synergistic effects of CA (up to 38 µM) and IM (up to 0.15 µM) on K562 cells.	CA induced apoptosis in IM-resistant cells and reduced their proliferation. Combination treatment with CA and IM showed synergistic effects, increasing the antiproliferative activity.	[114]
To assess the activity of Pancreatic Ductal Adenocarcinoma (PDAC) by treatment with CA, gemcitabine (Gem), and doxorubicin (DOX)	• In vitro: Human epithelioid carcinoma attached cell lines Panc-1 and Mia-PaCa-2. Both have increased potential of migration and invasion, as well as Gem resistance	Cytotoxic analysis of CA was measured at 24 and 48 h in combination with Gem and DOX.	CA showed cytotoxic concentrations (IC50) of 37.37 µM and 15.06 µM against Panc-1 and Mia-PaCa-2, respectively. Cotreatment with a combination of CA and Gem or DOX did not show synergic activity; in contrast, it showed antagonism, suggesting that CA could display interactions with Gem or DOX.	[135]
To study the effect of CA and DOX on lung cancer	• In vitro: mouse pulmonary system adenocarcinoma LA795 cell line • In vivo: Balb/c mice and Sprague Dawley (SD) rats	In vitro: Not specified In vivo: CA (5.4 mg/kg bw) + DOX (4.1 mg/kg bw)	In vitro: CA inhibited TMEM16A with an IC50 of 29.47 ± 3.19 μM. CA regulated the proliferation, migration, and apoptosis of lung cancer cells targeting TMEM16A (binding sites: D439, E448, and R753). CA regulated the growth of lung cancer through the MAPK pathway. CA + DOX inhibited lung cancer cell growth more than a double dose of either one. In vivo: CA + DOX achieved a tumor suppression rate of 85.6% and compensated for side effects.	[132]
To evaluate the effects of tocotrienols and CA encapsulated in a nanoemulsion with cisplatin on lung and liver cancer	• In vivo: human lung cancer cell A549 and liver HEP G2 cancer cells.	Not specified	TRF, CA, and CIS synergistically enhanced late-phase apoptosis and improved cell cycle arrest in the G0/G1 phase. ROS generation was enhanced using TRF:CA:CIS by 16.9% and 30.2% for A549 and HEP G2, respectively.	[129]
To evaluate the oxidative stress induced by multi-walled carbon nanotube (MWCNT) treatment on islets and β-cells.	• In vivo: islets and β-cells		CA significantly reduced ROS production after MWCNT treatment and increased insulin secretion together with the enzymes SOD, GSH-Px, CAT, and GSH, but it decreased the level of MDA.	[136]
To evaluate the effect of CA encapsulated in a nanoemulsion on the reduction of nephrotoxicity effects	• In vitro: non-cancer cells of the HEK 293 kidney line	CA (0.08–1.75 μM) + CIS 0.03 μM	Improved cell viability in kidney cells from 33% to over 95%.	[129]
To evaluate delivery systems with CA for the treatment of breast cancer, loaded on oxidant carbon nanotube (OCNT) and/or chitosan (CS).	• In vitro: human breast cancer MDA-MB-231 cell line	CA (100 µg/mL); oxidant carbon nanotube (OCNT)/CA (80 µg/mL); and chitosan (CS)/OCNT/CA (30 µg/mL)	The delivery system based on CS/OCNT/CA showed a higher cytotoxic effect on MDA-MB-231 compared to OCNT/CA and CA alone through apoptosis.	[137]