Ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by inhibition of drug resistance

Cancer is a severe health problem that continues to be a leading cause of death worldwide. Increasing knowledge of the molecular mechanisms underlying cancer progression has led to the development of a vast number of anticancer drugs. However, the use of chemically synthesized drugs has not significantly improved the overall survival rate over the past few decades. As a result, new strategies and novel chemoprevention agents are needed to complement current cancer therapies to improve efficiency. Naturally occurring compounds from plants known as phytochemicals, serve as vital resources for novel drugs and are also sources for cancer therapy. Some typical examples include taxol analogs, vinca alkaloids such as vincristine, vinblastine, and podophyllotoxin analogs. These phytochemicals often act via regulating molecular pathways which are implicated in growth and progression of cancer. The specific mechanisms include increasing antioxidant status, carcinogen inactivation, inhibiting proliferation, induction of cell cycle arrest and apoptosis; and regulation of the immune system. The primary objective of this review is to describe what we know to date of the active compounds in the natural products, along with their pharmacologic action and molecular or specific targets. Recent trends and gaps in phytochemical based anticancer drug discovery are also explored. The authors wish to expand the phytochemical research area not only for their scientific soundness but also for their potential druggability. Hence, the emphasis is given to information about anticancer phytochemicals which are evaluated at preclinical and clinical level.

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“…Ki-67, CD31, and miR-29a (Prasad et al, 2012;Zhang et al, 2018) Withaferin-A (phytosterols) Withania somnifera (Solanaceae)…”

Section: Phytochemicals In Pre-clinical Trialsmentioning

confidence: 99%

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

et al. 2020

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“…## P < 0:01 is considered very significant; ### P < 0:001 is considered highly significant. 5 Oxidative Medicine and Cellular Longevity combination treatment of CREE and UA is found and shown to enhance the efficacy and reduce the side effects. Significant improvement in body weight, levels of serum insulin, liver glycogen, and antioxidant enzymes activity were observed with best effect in the combined treatment group rather than the single drug treatment group.…”

Section: Resultsmentioning

confidence: 99%

“…Various recently studies reported the wide spectrum pharmacological potentials of UA. It exhibits a variety of effects including antimicrobial, anti-arthritic, and anticancer effects against variety of cancers [4,5]. Numerous bioactivities of UA have been reported, but till date no clinical work available which demonstrates beneficial effects to human health care.…”

Section: Introductionmentioning

confidence: 99%

Catharanthus roseus Combined with Ursolic Acid Attenuates Streptozotocin-Induced Diabetes through Insulin Secretion and Glycogen Storage

Alkreathy

Ahmad

2020

Oxidative Medicine and Cellular Longevity

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Catharanthus roseus (C. roseus) and ursolic acid (UA) are ayurvedic medicines with multiple pharmacological activities including antidiabetic activity, but till date, no study is available on their combination. This study documented the antidiabetic efficacy of the combination of C. roseus and UA in rats. Rats were divided into six groups. All groups were given a single dose of Streptozotocin (STZ) at a dose of 50 mg/kg by intraperitoneal route for induction of diabetes, except the normal control group. Group 1 was treated as a normal control (NC) group and fed with saline water, Group 2 as a Diabetes Control group, Group 3 as a STZ+C. roseus ethanolic extract (CREE) group at 50 mg/kg p.o., Group 4 as a STZ+UA group orally at 50 mg/kg, Group 5 as a STZ+CREE (25 mg/kg p.o.)+UA (25 mg/kg p.o.) group, and Group 6 as a STZ+Glimepiride (0.1 mg/kg) group. Diabetes was confirmed after 72 hours by estimation of blood glucose level, and then treatment was given for the next 28 days. During the course of treatment, plasma insulin and blood glucose were measured regularly at the interval of 7 days. At the end of the protocol, blood was collected and animals were sacrificed. The glucose level, insulin level, liver glycogen storage level, and antioxidant enzymes (LPO, CAT, SOD, GPx, GST) were measured. The blood glucose level in Group 5 significantly (P<0.001) reduced to 98.35±2.45 mg/dl in comparison with that in Group 2 (321.75±5.46 mg/dl). The level of plasma insulin in Group 5 increased (13.65±0.10 μU/ml) significantly (P<0.01) as compared with that in Group 2 (05.93±0.31 μU/ml). In Group 5, the level of glycogen in liver was significantly (P<0.01) increased as compared with that in Group 2 rats. The level of antioxidant enzymes in Group 5 restored toward normal values significantly (P<0.01; P<0.001) as compared with that in Group 2 animals. These findings suggest that low-dose combination of CREE and UA is effective in the treatment of diabetes.

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“…Oxaliplatin, which is commonly used for treating colon carcinoma, had been reported to affect tumor cell glucose metabolism. 29,30 We next examined the effect of oxaliplatin on YY1 and GLUT3 expression. As shown in Figure 4D, oxaliplatin grossly suppressed the expression levels of both YY1 and GLUT3 in HCT116 p53null cells in a dose-dependent manner.…”

Section: Yin Yang 1 Enhances Tumor Cell Glycolysis In a P53-indepenmentioning

confidence: 99%

Yin Yang 1 promotes the Warburg effect and tumorigenesis via glucose transporter GLUT3

Wang

Huang

et al. 2018

Cancer Science

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Cancer cells typically shift their metabolism to aerobic glycolysis to fulfill the demand of energy and macromolecules to support their proliferation. Glucose transporter (GLUT) family‐mediated glucose transport is the pacesetter of aerobic glycolysis and, thus, is critical for tumor cell metabolism. Yin Yang 1 (YY1) is an oncogene crucial for tumorigenesis; however, its role in tumor cell glucose metabolism remains unclear. Here, we revealed that YY1 activates GLUT3 transcription by directly binding to its promoter and, concomitantly, enhances tumor cell aerobic glycolysis. This regulatory effect of YY1 on glucose entry into the cells is critical for YY1‐induced tumor cell proliferation and tumorigenesis. Intriguingly, YY1 regulation of GLUT3 expression, and, subsequently, of tumor cell aerobic glycolysis and tumorigenesis, occurs p53‐independently. Our results also showed that clinical drug oxaliplatin suppresses colon carcinoma cell proliferation by inhibiting the YY1/GLUT3 axis. Together, these results link YY1's tumorigenic potential with the critical first step of aerobic glycolysis. Thus, our novel findings not only provide new insights into the complex role of YY1 in tumorigenesis but also indicate the potential of YY1 as a target for cancer therapy irrespective of the p53 status.

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Ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by inhibition of drug resistance

Cited by 54 publications

References 28 publications

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

Catharanthus roseus Combined with Ursolic Acid Attenuates Streptozotocin-Induced Diabetes through Insulin Secretion and Glycogen Storage

Yin Yang 1 promotes the Warburg effect and tumorigenesis via glucose transporter GLUT3

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