Chemotherapy might cure cancer, but it can give patients cancer, too. Fortunately, there are powerful botanicals that have the potential to make chemotherapy more effective and far less dangerous.

Andrographis reverses gemcitabine resistance through regulation of ERBB3 and calcium signaling pathway in pancreatic ductal adenocarcinoma. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, primarily due to intrinsic or acquired resistance to chemotherapy, such as Gemcitabine (Gem). Naturally occurring botanicals, including Andrographis (Andro), can help enhance the anti-tumorigenic therapeutic efficacy of conventional chemotherapy through time-tested safety and cost effectiveness. Accordingly, we hypothesized that Andro might reverse Gem resistance in PDAC. The critical regulatory pathways associated with Gem resistance in PDAC were identified by analyzing publicly available transcriptomic profiling and PDAC tissue specimens. A series of systematic in vitro experiments were performed using Gem-resistant (Gem-R) PDAC cells and patient derived 3D-organoids to evaluate the Andro-mediated reversal of Gem resistance in PDAC. Transcriptomic profiling identified the calcium signaling pathway as a critical regulator of Gem-resistance (Fold enrichment: 2.8, p = 0.002). Within this pathway, high ERBB3 expression was significantly associated with poor prognosis in PDAC patients. The combination of Andro and Gem exhibited superior anti-cancer potential in Gem-R PDAC cells through potentiating cellular apoptosis. The combined treatment down-regulated ERBB3 and decreased intracellular calcium concentration in Gem-R PDAC cells. Finally, these findings were successfully interrogated in patient-derived 3D-organoids. In conclusion, we demonstrate novel evidence for Andro-mediated reversal of chemoresistance to Gem in PDAC cells through the regulation of ERBB3 and calcium signaling. [Okuno K, Xu C, Pascual-Sabater S, et al. Andrographis reverses gemcitabine resistance through regulation of ERBB3 and calcium signaling pathway in pancreatic ductal adenocarcinoma. Biomedicines. 2023;11:119.]

Andrographis-mediated chemosensitization through activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways in colorectal cancer. Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality in the USA. As much as 50–60% of CRC patients develop resistance to 5-fluorouracil (5FU)-based chemotherapeutic regimens, attributing the increased overall morbidity and mortality. In view of the growing evidence that active principles in various naturally occurring botanicals can facilitate chemosensitization in cancer cells, herein, we undertook a comprehensive effort in interrogating the activity of one such botanical—andrographis—by analyzing its activity in CRC cell lines [both sensitive and 5FU resistant (5FUR)], a xenograft animal model and patient-derived tumor organoids. We observed that combined treatment with andrographis was synergistic and resulted in a significant and dose-dependent increase in the efficacy of 5FU in HCT116 and SW480 5FUR cells (P < 0.05), reduced clonogenic formation (P < 0.01) and increased rates of caspase-9-mediated apoptosis (P < 0.05). The genomewide expression analysis in cell lines led us to uncover that activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways were the key mediators for the anti-cancer and chemosensitizing effects of andrographis. Subsequently, we validated our findings in a xenograft animal model, as well as two independent CRC patient-derived organoids—which confirmed that combined treatment with Andrographis was significantly more effective than 5FU and andrographis alone and that these effects were in part orchestrated through dysregulated expression of key genes (including HMOX1, GCLC, GCLM and TCF7L2) within the ferroptosis and Wnt-signaling pathways. Collectively, our data highlight that andrographis might offer a safe and inexpensive adjunctive therapeutic option in the management of CRC patients. [Sharma P, Shimura T, Banwait JK, Goel A. Andrographis-mediated chemosensitization through activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways in colorectal cancer. Carcinogenesis. 2020:1-10.]

Andrographis overcomes 5-fluorouracil associated chemoresistance through inhibition of DKK1 in colorectal cancer. Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths in the US. 5-fluorouracil (5FU)-based chemotherapeutic drug remains a mainstay of CRC treatment. Unfortunately, ~50-60% of patients eventually develop resistance to 5FU, leading to poor survival outcomes. Our previous work revealed that andrographis enhanced 5FU-induced anti-cancer activity, but the underlying mechanistic understanding largely remains unclear. In this study, we first established 5FU resistant (5FUR) CRC cells and observed that combined treatment with andrographis-5FU in 5FUR cells exhibited superior effect on cell viability, proliferation and colony formation capacity compared to individual treatments (p<0.001). To identify key genes and pathways responsible for 5FU resistance, we analyzed genome-wide transcriptomic profiling data from CRC patients who either responded or did not respond to 5FU. Among a panel of differentially expressed genes, DKK1 overexpression was a critical event for 5FU resistance. Moreover, andrographis significantly downregulated 5FU-induced DKK1 overexpression, accompanied with enhanced anti-tumor effects by abrogating downstream Akt-phosphorylation. In line with in vitro findings, andrographis enhanced 5FU-induced anti-cancer activity in mice xenografts and patient-derived tumoroids (p<0.01). In conclusion, our data provide novel evidence for andrographis-mediated reversal of 5FU resistance, highlighting its potential role as an adjunct to conventional chemotherapy in CRC. [Zhao Y, Wang C, Goel A. Andrographis overcomes 5-fluorouracil associated chemoresistance through inhibition of DKK1 in colorectal cancer. Carcinogenesis. 2021. Advanced publication data: https://doi.org/10.1093/carcin/bgab027]

Berberine overcomes gemcitabine-associated chemoresistance through regulation of Rap1/PI3K-Akt signaling in pancreatic ductal carcinoma. Abstract: Gemcitabine (Gem)-based chemotherapy is one of the first-line treatments for pancreatic ductal adenocarcinoma (PDAC). However, its clinical effect is limited due to development of chemoresistance. Various naturally occurring compounds, including Berberine (BBR), provide an anti-cancer efficacy with time-tested safety, individually and in combination with chemotherapeutic drugs. Accordingly, we hypothesized that BBR might enhance the chemosensitivity to Gem in PDAC. In this study, cell culture studies using MIA PaCa-2 and BxPC-3 cells, followed by analysis in patient derived organoids were performed to evaluate the anti-cancer effects of BBR in PDAC. Considering that cancer is a significant manifestation of increased chronic inflammatory stress, systems biology approaches are prudent for the identification of molecular pathways and networks responsible for phytochemical-induced anti-cancer activity, we used these approaches for BBR-mediated chemosensitization to Gem. Firstly, Gem-resistant (Gem-R) PDAC cells were established, and the combination of BBR and Gem revealed superior anti-cancer efficacy in Gem-R cells. Furthermore, the combination treatment induced cell cycle arrest and apoptosis in Gem-R PDAC cells. Transcriptomic profiling investigated the Rap1 and PI3K-Akt signaling pathway as a key regulator of Gem-resistance and was a key mediator for BBR-mediated chemosensitization in PDAC cells. All cell culture-based findings were successfully validated in patient-derived organoids. In conclusion, we demonstrate that BBR-mediated reversal of chemoresistance to Gem manifests through Rap1/PI3K-Akt signaling in PDAC. [Okuno K, Xu C, Pascual-Sabater S, et al. Berberine overcomes gemcitabine-associated chemoresistance through regulation of Rap1/PI3K-Akt signaling in pancreatic ductal carcinoma. Pharmaceuticals. 2022;15:1199.]

Curcumin as adjuvant therapy to improve remission in myeloma patients: a pilot randomized trial. Background: The treatment for ineligible transplant multiple myeloma is melphalan prednisone. Curcumin has an anti-inflammatory and antiangiogenesis in cancer-directed to nuclear factor-kappa B (NF-kB) pathway. Interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and lactate dehydrogenase (LDH) were also involved in the pathogenesis of myeloma. No clinical study has evaluated the efficacy of curcumin in myeloma patients. To evaluate the efficacy of curcumin as adjuvant into melphalan prednisone in myeloma patients Methods: 33 myeloma patients at Dr. Kariadi General Hospital, Semarang, Indonesia during 2016-2017 were randomly assigned single-blindedly into MPC (n=17) and control group (n=16). The MPC group was treated with melphalan 4 mg/m2, prednisone 40 mg/m2 for 7 days, and curcumin 8 gram daily for 28 days. The MP control group was treated with melphalan, prednisone, and placebo. The primary endpoint was the overall remission. Pre and post-treatment was examined for NF-κB, VEGF, TNF-α, IL-6, LDH, and CRP levels All data analyses were per protocol. Results: There was a significant difference in overall remission between the MPC and MP control groups [75%vs 33.3%, x2=6.89, P=0.009]. A significant decrease of NF-κB, VEGF, TNF-α levels were shown in the MPC group compared with the MP control group. There was a significant decrease in IL-6 levels in a subgroup analysis of the MPC group. TNF-α levels had a significant correlation with remission [OR=1.35; (95%CI=1.03-1.76); P=0.03]. Conclusion: Curcumin has an efficacy in improving overall remission and decreasing NF-κB, VEGF, TNF-α, and IL-6 levels in myeloma patients. [Santosa D, Suharti C, Riwant I, et al. Curcumin as adjuvant therapy to improve remission in myeloma patients: a pilot randomized clinical trial. Casp J Int Med. 2022;13: 375-384.]

Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Development of resistance to chemotherapeutic drugs is a major challenge in the care of patients with pancreatic ductal adenocarcinoma (PDAC). Acquired resistance to chemotherapeutic agents in PDAC has been linked to a subset of cancer cells termed ‘cancerstem cells’ (CSCs). Therefore, an improved understanding of the molecular events underlying the development of pancreatic CSCs is required to identify new therapeutic targets to overcome chemoresistance. Accumulating evidence indicates that curcumin, a phenolic compound extracted from turmeric, can overcome de novo chemoresistance and re-sensitize tumors to various chemotherapeutic agents. However, the underlying mechanisms for curcumin-mediated chemosensitization remain unclear. The Enhancer of Zeste Homolog-2 (EZH2) subunit of Polycomb Repressive Complex 2 (PRC2) was recently identified as a key player regulating drug resistance. EZH2 mediates interaction with several long non-coding RNAs (lncRNAs) to modulate epithelial-mesenchymal transition and cancer stemness, phenomena commonly associated with drug resistance. Here, we report the re-sensitization of chemoresistant PDAC cells by curcumin through the inhibition of the PRC2-PVT1-c-Myc axis. Using gemcitabine-resistant PDAC cell lines, we found that curcumin sensitized chemoresistant cancer cells by inhibiting the expression of the PRC2 subunit EZH2 and its related lncRNA PVT1. Curcumin was also found to prevent the formation of spheroids, a hallmark of CSCs, and to down-regulate several self-renewal driving genes. In addition, we confirmed our in vitro findings in a xenograft mouse model where curcumin inhibited gemcitabine-resistant tumor growth. Overall, this study indicates clinical relevance for combining curcumin with chemotherapy to overcome chemoresistance in PDAC. [Yoshida K, Toden S, Ravindranathan P, Han H, Goel A. Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Carcinogenesis. 2017 Oct 1;38(10):1036-1046.]

Chemoprevention and Treatment Efficacy of Curcumin in Combination with Metformin in an in Vivo Oral Carcinogenesis Model. Evaluation of the efficacy of [BCM-95] Curcumin and Metformin in prevention of oral pre-malignant lesion (PML) progression. The animal model was established using 4-6 weeks C57BI/6 mice (N=60); the mice were divided into control arm (N=10) with plain drinking water and the treatment arm (N=50) which received the cancer causing 4-nitroquinoline-oxide. After 17 weeks, the mice were taken off the carcinogen and divided into 4 groups: arm 1 with plain water, arm 2 with curcumin, arm 3 with the drug metformin, and arm 4 with a combination of both curcumin and metformin. The mice were examined at 17th week as well as at the end of the 25 week study period, and samples collected for molecular analysis. The average tumor volume was reduced in the combination arm (0.693±0.034) and the individual arms (curcumin 2.45; metformin 1.45±0.33) as compared to the 4NQO arm (6.65±2.37). The average number of lesions (malignant tumors) per mouse was also reduced in the combination arm (Avg 0.375) and the curcumin arm (Avg 0.25) as compared to the 4NQO arm (Avg 0.8). The overall survival of the combination arm was better when compared to individual treatment (p= 0.0006). The animals in the water control arm remained healthy. Curcumin reduced tumor formation both on its own and in conjunction with metformin. Conclusion: The clinical results suggest that the combination arm is more efficient in chemoprevention. Further studies using the molecular markers and subsequent functional studies are currently ongoing. [Siddappa G, Ravindra D, Kulsum S, et al. Chemoprevention and Treatment Efficacy of Curcumin in Combination with Metformin in an in Vivo Oral Carcinogenesis Model. 5th International Federation of Head and Neck Oncologic Societies (IFHNOS). July 26th-30th 2014, New York, NY. Also presented at the 13th National Conference of Foundation for Head and Neck Oncology (FHNO). September 27th – 29th 2013, JAIPUR.]

Curcumin-mediated resistance to Lenvatinib via EGFR signaling pathway in hepatocellular carcinoma. Lenvatinib is a multi-kinase inhibitor approved as a first-line treatment for patients with unresectable advanced hepatocellular carcinoma (HCC). However, its response rate is unsatisfactory, primarily due to the acquisition of resistance which limits its clinical significance for treating patients with HCC. Recent evidence suggests that EGFR activation can trigger Lenvatinib-resistance; and is considered an important therapeutic target in HCC. Curcumin, one of the most studied naturally occurring botanicals with robust anti-cancer activity, is also reported to be a potent tyrosine kinase inhibitor. In this study, we hypothesized that the anti-EGFR potential of Curcumin might help overcome Lenvatinib resistance in HCC. We established two Lenvatinib-resistant cells and discovered that a combination of Curcumin and Lenvatinib exhibited a synergistic anti-tumor efficacy in the resistant HCC cell lines. In line with previous reports, Lenvatinib-resistant cell lines revealed significant activation of the EGFR, and genomewide transcriptomic profiling analysis identified that the PI3K-AKT pathway was associated with Lenvatinib resistance. The combination treatment with Curcumin and Lenvatinib dramatically suppressed gene and protein expression of the EGFR-PI3K-AKT pathway, suggesting Curcumin overcomes Lenvatinib resistance via inhibition of EGFR. We further validated these findings in tumor spheroids derived from resistant cell lines. In conclusion, we, for the first time, report that Curcumin reverses Lenvatinib resistance in HCC, and their combination has clinical application potential for adjunctive treatment in HCC. [Miyazaki K, Morine Y, Xu C, et al. Curcumin-mediated resistance to Lenvatinib via EGFR signaling pathway in hepatocellular carcinoma Cells. 2023;12.]

Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Development of resistance to chemotherapeutic drugs is a major challenge in the care of patients with pancreatic ductal adenocarcinoma (PDAC). Acquired resistance to chemotherapeutic agents in PDAC has been linked to a subset of cancer cells termed ‘cancerstem cells’ (CSCs). Therefore, an improved understanding of the molecular events underlying the development of pancreatic CSCs is required to identify new therapeutic targets to overcome chemoresistance. Accumulating evidence indicates that curcumin, a phenolic compound extracted from turmeric, can overcome de novo chemoresistance and re-sensitize tumors to various chemotherapeutic agents. However, the underlying mechanisms for curcumin-mediated chemosensitization remain unclear. The Enhancer of Zeste Homolog-2 (EZH2) subunit of Polycomb Repressive Complex 2 (PRC2) was recently identified as a key player regulating drug resistance. EZH2 mediates interaction with several long non-coding RNAs (lncRNAs) to modulate epithelial-mesenchymal transition and cancer stemness, phenomena commonly associated with drug resistance. Here, we report the re-sensitization of chemoresistant PDAC cells by curcumin through the inhibition of the PRC2-PVT1-c-Myc axis. Using gemcitabine-resistant PDAC cell lines, we found that curcumin sensitized chemoresistant cancer cells by inhibiting the expression of the PRC2 subunit EZH2 and its related lncRNA PVT1. Curcumin was also found to prevent the formation of spheroids, a hallmark of CSCs, and to down-regulate several self-renewal driving genes. In addition, we confirmed our in vitro findings in a xenograft mouse model where curcumin inhibited gemcitabine-resistant tumor growth. Overall, this study indicates clinical relevance for combining curcumin with chemotherapy to overcome chemoresistance in PDAC. [Yoshida K, Toden S, Ravindranathan P, Han H, Goel A. Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Carcinogenesis. 2017 Oct 1;38(10):1036-1046.]

Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Resistance to cytotoxic chemotherapy is a major cause of mortality in colorectal cancer (CRC) patients. Chemoresistance has been linked primarily to a subset of cancer cells undergoing epithelial-mesenchymal transition (EMT). Curcumin, a botanical with anti-tumorigenic properties, has been shown to enhance sensitivity of cancer cells to chemotherapeutic drugs, but the molecular mechanisms underlying this phenomenon remain unclear. Effects of curcumin and 5-fluorouracil (5FU) individually, and in combination, were examined in parental and 5FU resistant (5FUR) cell lines. We performed a series of growth proliferation and apoptosis assays in 2D and 3D cell cultures. Furthermore, we identified and analyzed the expression pattern of a subset of putative EMT-suppressive microRNAs (miRNAs) and their downstream target genes regulated by curcumin. Chemosensitizing effects of curcumin were validated in a xenograft mouse model. Combined treatment with curcumin and 5FU enhanced cellular apoptosis and inhibited proliferation in both parental and 5FUR cells, while 5FU alone was ineffective in 5FUR cells. A group of EMT-suppressive miRNAs were upregulated by curcumin treatment in 5FUR cells. Curcumin suppressed EMT in 5FUR cells by downregulating BMI1, SUZ12 and EZH2 transcripts, key mediators of cancer stemness-related polycomb repressive complex subunits. Using a xenograft and mathematical models we further demonstrated that curcumin sensitized 5FU to suppress tumor growth. We provide novel mechanistic evidence for curcuminmediated sensitization to 5FU-related chemoresistance through suppression of EMT in 5FUR cells via upregulation of EMT-suppressive miRNAs. This study highlights the potential therapeutic usefulness of curcumin as an adjunct in patients with chemoresistant advanced CRC. [Toden S, Okugawa Y, Jascur T, Wodarz D, Komarova NL, Buhrmann C, Shakibaei M, Boland, Goel A. Curcumin mediates chemsensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis. 2015 Feb 4

Curcumin potentiates antitumor activity of 5-fluorouracil in a 3D alginate tumor microenvironment of colorectal cancer. BACKGROUND: To overcome the limitations of animal-based experiments, 3D culture models mimicking the tumor microenvironment in vivo are gaining attention. Herein, we investigated an alginate-based 3D scaffold for screening of 5-fluorouracil (5-FU) or/and curcumin on malignancy of colorectal cancer cells (CRC). METHODS: The potentiation effects of curcumin on 5-FU against proliferation and metastasis of HCT116 cell and its corresponding isogenic 5-FU-chemoresistant cells (HCT116R) were examined in a 3D-alginate tumor model. RESULTS: CRC cells encapsulated in alginate were able to proliferate in 3D-colonospheres in a vivo-like phenotype and invaded from alginate. During cultivation of cells in alginate, we could isolate 3 stages of cells, (1) alginate proliferating (2) invasive and (3) adherent cells. Tumor-promoting factors (CXCR4, MMP-9, NF-κB) were significantly increased in the proliferating and invasive compared to the adherent cells, however HCT116R cells overexpressed factors in comparison to the parental HCT116, suggesting an increase in malignancy behavior. In alginate, curcumin potentiated 5-FU-induced decreased capacity for proliferation, invasion and increased more sensitivity to 5-FU of HCT116R compared to the HCT116 cells. IC50 for HCT116 to 5-FU was 8nM, but co-treatment with 5 μM curcumin significantly reduced 5-FU concentrations in HCT116 and HCT116R cells (0.8nM, 0.1nM, respectively) and these effects were accompanied by down-regulation of NF-κB activation and NF-κB-regulated gene products. CONCLUSIONS: Our results demonstrate that the alginate provides an excellent tumor microenvironment and indicatethat curcumin potentiates and chemosensitizes HCT116R cells to 5-FU-based chemotherapy that may be useful for the treatment of CRC and to overcome drug resistance. [Shakibaei M, Kraehe P, Popper B, Shayan P, Goel A, Buhrmann C. Curcumin potentiates antitumor activity of 5-flurouracil in a 3D alginate tumor microenvironment of colorectal cancer. BMC Cancer. 2015 Apr 10;15:250.]

Curcumin chemosensitizes 5-Fluorouracil resistant MMR-deficient human colon cancer cells in high density cultures. More than 15% of colorectal cancer (CRC) patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50-60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permit regeneration of original tumors. This study investigated the effectiveness of 5-FU and BCM-95 Curcumin in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells. Pre-treatment with BCM-95 curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures; however, MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells. The results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population. [Shakibaei M, Buhrmann C, Kraehe P, Shayan P, Lueders C and Goel A. Curcumin chemosensitizes 5-Fluorouracil resistant MMR-deficient human colon cancer cells in high density cultures. PLoS ONE. 2014:9(1).]

Oligomeric proanthocyanidins (OPCs) from grape seed extract suppress the activity of ABC transporters in overcoming chemoresistance in colorectal cancer cells. Multidrug resistance is a major hindrance in managing cancer. By performing a series of experiments in chemoresistant colorectal cancer cell lines, we demonstrate that oligomeric proanthocyanidins (OPCs) from grape seed extracts (VX1®) can sensitize both acquired (HCT116-FOr cells) and innately chemoresistant (H716 cells) cancer cells to chemotherapeutic drugs, 5-fluorouracil (5FU) and oxaliplatin, by inhibiting ABC transporter proteins. When combined with chemotherapeutic drugs, OPCs significantly inhibited growth of the chemoresistant cells (p<0.05 to p<0.001), and decreased the expression of several key ABC transporters. Moreover, the activity of the ABC transporters was also significantly decreased by OPCs in the cell lines (p<0.05). We further confirmed that co-treatment with OPCs sensitized the chemoresistant cells to 5FU and oxaliplatin, as observed by improvement in cell cycle arrest, double strand breaks and p53 accumulation in these cells. Additionally, we confirmed that co-administration of OPCs with chemotherapeutic drugs significantly decreased chemoresistant xenograft tumor growth in mice (p<0.05). Together, our study illuminates the downregulation of multiple ABC transporters as a mechanism by which OPCs overcome chemoresistance in cancer cells, and may serve as adjunctive treatments in patients with refractory colorectal cancer. [Ravindranathan P, Pasham D, Goel A. Oligomeric proanthocyanidins (OPCs) from grape seed extract suppress the activity of ABC transporters in overcoming chemoresistance in colorectal cancer cells. Carcinogenesis. 29 Dec 2018. https://doi.org/10.1093/carcin/bgy184]