Tagged: Top-Performer

An Overview of Cannabis and Cancer

Researchers review different varieties of cannabinoids, the signaling pathways they affect, and their role in different types of cancer.

Close up of female Cannabis flower with a high production of cannabinoid resin
Close up of female Cannabis flower with a high production of cannabinoid resin

The Top-Performer series highlights research literature published in Oncotarget that has generated a high Altmetric score. Altmetric scores, located at the top-left of trending Oncotarget papers, provide an at-a-glance indication of the volume and type of online attention the research has received. Read Oncotarget’s Top 100 Altmetric papers.

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In a high-rated paper published in 2014 in Oncotarget, researchers from India’s Sanjay Gandhi Post Graduate Institute of Medical Sciences and the United States’ Ohio State University reviewed cannabinoids, their role in different types of cancer, and the signaling pathways they affect. Today, this paper currently presents with an Altmetric Attention score of 200.

“In this review article, we will focus on a broad range of cannabinoids, their receptor dependent and receptor independent functional roles against various cancer types with respect to growth, metastasis, energy metabolism, immune environment, stemness and future perspectives in exploring new possible therapeutic opportunities.”

Cannabinoids and Receptors

“[The] Cannabis sativa plant has been used for several hundreds of years both recreationally and medicinally.”

Researchers trace the earliest archaeological evidence of cannabis medical use back to ancient China, during the Han Dynasty. The use of this plant was recommended for rheumatic pain, constipation, disorders of the female reproductive tract, and malaria, among other conditions. Cannabis sativa contains three major classes of bioactive molecules; flavonoids, terpenoids, and 100+ types of cannabinoids. 

Cannabinoids are a family of complex chemicals that activate and bind to two receptors in mammals named central cannabinoid receptor one (CB1) and peripheral cannabinoid receptor two (CB2). These receptors are found abundantly throughout the central nervous system and immune system.

“CB1/2 receptors are also responsible for proliferation, motility, invasion, adhesion and apoptosis of cancer cells both in vitro and in vivo.”

CB1 and CB2 receptors have been used as targets for the treatment of various diseases, including neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease, neuropathic and inflammatory pain, glaucoma, multiple sclerosis, cardiovascular disorders, obesity, and more. Today, in addition to inhibiting nausea and emesis, stimulating appetite, improving mood, and relieving pain and insomnia that cancer patients face, cannabinoids used in the targeted killing of tumor cells has been a major discovery in cancer treatment. 

“In this review article we focused on the role of cannabinoids in different cancer types and the respective signaling pathways.”

Endocannabinoids

“Endogenous cannabinoids which are produced in our body include lipid molecules containing long-chain polyunsaturated fatty acids, amides, esters and ethers that bind to CB1 or CB2 receptors.”

Endocannabinoids act primarily as neuromodulators, or reverse messengers, which can affect the release of neurotransmitters. They also play important role in regulating inflammation, insulin, and fat and energy metabolism, which affects our mood, appetite, pain sensation, inflammation response, and memory. 

Phytocannabinoids

“Phytocannabinoids are only known to occur naturally in significant quantities in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes.”

Over 120 phytocannabinoids are capable of interacting within the body’s own biological systems because their structures and behaviors mimic those of endocannabinoids (cannabinoids that are synthesized by our own bodies). The most prevalent natural cannabinoids are delta-9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), and cannabinol (CBN). 

Synthetic Cannabinoids

“Synthetic cannabinoids are classified on the basis of chemical structure of molecules and they are capable of a more selective activation of cannabinoid receptors [28].”

The researchers explain that synthetic cannabinoids have been used extensively in pharmacology to gain better insight about their action in order to evaluate the potential use of cannabinoids clinically. 

Within the synthetic category, classical cannabinoids are compounds isolated from the Cannabis sativa plant or its synthetic analogs. Nonclassical cannabinoids “are a family of AC-bicyclic and ACD-tricyclic cannabinoid analogs.” Aminoalkylindoles are non-cannabinoid molecules given cannabis-mimicking capabilities. Eicosanoids are compounds that can enhance or inhibit physiological and pathophysiological responses. These lipid mediators also have an affinity for CB1 and CB2 receptors.

Cannabinoids in Cancer

Multiple studies have shown that THC, CBD, and synthetic cannabinoids can inhibit breast cancer cell proliferation and drive them toward apoptosis.

“It [breast cancer] is classified into three main subtypes according to their molecular profiles: hormone receptor-positive, HER2-positive (ErbB2-positive, a member of EGFR family) and triple-negative tumors [42-43]. Cannabinoid-based medicines have been useful for the treatment of these three breast cancer subtypes.”

In prostate cancer, CB1 and CB2 expression levels are often higher in prostate cancer tissues and several cell lines compared to normal prostate epithelial cells. Studies have found that cannabinoids have either induced cell death or activated pathways that lead to growth inhibition and increased patient survival.

Preclinical cancer models have shown that cannabinoids can alter gene expression, block enzymes, inhibit signaling pathways, and induce apoptosis in mice with lung cancer. In skin and pancreatic cancers, researchers have found that the activation of CB1/2 receptors induced the apoptotic death of tumorigenic cells, without affecting the normal cells. In bone cancer studies, researchers found that cannabinoids reduced pain and bone loss in mice.

“Cannabinoids could halt tumor development without side effects via specific targeting of CB1/CB2 receptor.”

Cannabinoids have anti-tumorigenic properties in glioma, lymphoma, oral cancers, and thyroid carcinoma. In young people, marijuana smoking has been found to increase the incidence of head and neck cancer, however, cannabinoids have anti-tumor properties.

Conclusion

“Cannabinoids exert a direct anti-proliferative effect on tumors of different origin.”

Given that cannabinoid receptors are often demonstrated to be expressed higher in tumor cells than in normal cells, cannabinoids are more specific to cancer cells than to normal cells. The researchers conclude their review by noting that it is important to identify which cannabinoids are most compatible with an individual cancer or disorder to have the greatest impact on patient outcome.

“It is important to understand which of the cannabinoid receptors are expressed and activated in different tumors as each receptor follows a different signaling mechanism.”

Years after this paper was published, subsequent studies have confirmed and expanded on many ideas mentioned in this review, including the regenerative and pharmacological effects of THC, synthetic cannabis used to treat thrombosis, increased expression of CB2 potentially linked to colon cancer, experiments with cannabis extracts, synergistic combinations of cannabinoids, and much more. 

Click here to read the full scientific review, published in Oncotarget.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.

Sunscreen Ingredient Promotes Breast Cancer in Diet-Dependent Manner

In this high-Altmetric scoring Oncotarget paper, researchers examined the in vivo activity of benzophenone-3—a common ingredient in sunscreen and an endocrine-disrupting chemical—in a dietary context in mice to determine its potential role in promoting breast cancer.

In this high-Altmetric scoring Oncotarget paper, researchers examined the in vivo activity of benzophenone-3—a common ingredient in sunscreen and an endocrine-disrupting chemical—in a dietary context in mice to determine its potential role in promoting breast cancer.

Figure 2: BP-3 increased the proportion of epithelial tumors in mice fed an adult-restricted HFD.
Figure 2: BP-3 increased the proportion of epithelial tumors in mice fed an adult-restricted HFD.

The Top-Performer series highlights research literature published in Oncotarget that has generated a high Altmetric score. Altmetric scores, located at the top-left of trending Oncotarget papers, provide an at-a-glance indication of the volume and type of online attention the research has received. Read Oncotarget’s Top 100 Altmetric papers.

Listen to an audio version of this article

Benzophenone-3 (BP-3 or oxybenzone) has been identified as a known endocrine-disrupting chemical (EDC) and, alarmingly, it is a common ingredient in many modern brands of sunscreen. BP-3 is also present in household dust, fish lipids, and due to its widespread human use, the water environment. Previous studies have shown that environmental toxins and estrogenic chemicals have emerged as potential culprits in the promotion of breast cancer. BP-3 in particular has been known to have estrogenic and anti-estrogenic properties.

“Although BP-3 has a very short half-life, its presence is widespread in human urine [9], in as much as 98% of the general U.S. population [13].”

Researchers, from the Breast Cancer and the Environment Research Program at Michigan State University, authored the paper, titled: “Benzophenone-3 promotion of mammary tumorigenesis is diet-dependent.” This study currently presents with an Altmetric Attention score of 65.

“We [previously] demonstrated enhancement of mammary tumorigenesis by a diet high in saturated animal fat (HFD) [58]. Thus, examination of the activity of EDCs in a dietary context may provide additional insight into the potential role of EDCs in promoting breast cancer.”

The Study

“We have shown that both estrogen [15, 16] and HFD [17, 5] can modulate proliferative, inflammatory and angiogenic activity in the mammary gland.” 

The researchers previously demonstrated the effects of a high-fat diet (HFD) in breast cancer. In the current study, they examined BP-3 in mice under three dietary conditions: mice fed a life-long low-fat diet (LFD), mice fed a low-fat diet during puberty and then a high-fat diet in adulthood (LFD-HFD), and mice fed a high-fat diet during puberty and then a low-fat diet in adulthood (HFD-LFD). 

Using the Trp53null transplantation model of basal-like breast cancer, both pubertal and adult mice were first placed on a LFD or HFD. Half of the mice were injected with BP-3, ovariectomized, given time for recovery and the natural dissipation of endogenous hormones, and then they were treated with 17β-estradiol (E2; estrogen) for five days. 

“This study identifies the effects of BP-3 on mammary tumorigenesis with high-fat diet during puberty versus adulthood in Trp53null transplant BALB/c mice. Thus, it is logical to test their individual and combined effects on mammary tumorigenesis.”

The mice in both variations of the HFD and LFD were fed their initial diet from three to ten weeks of age, and then switched to the other diet. Half of the mice were injected with BP-3 and the other half were used as the control groups.

“As BP-3 has known estrogenic and anti-estrogenic properties [9], and our studies herein show BP-3 enhanced estrogen-stimulated mammary proliferation, we examined estrogen levels in plasma from sacrificed tumor-bearing mice.”

Results

“We found that BP-3 had complex effects that were dependent upon dietary regimen and tumor histopathology.”

Consistent with the researchers’ earlier studies, most of the tumors in mice were epithelial in composition and some were spindle cell carcinomas. The LFD-HFD combination resulted in an increased proportion of spindle cell tumors compared to the LFD, however, the proportion of epithelial versus spindle cell tumors was also increased by BP-3 treatment in mice fed the LFD-HFD. 

“BP-3 did not significantly alter apoptosis, except for spindle cell tumors arising in mice fed LFD (Figure 6). Apoptosis in spindle cell tumors from LFD + BP-3 mice was reduced by half compared to those from LFD mice (Figure 6B).”

“Kaplan-Meier analysis revealed that BP-3 reduced tumorigenesis of epithelial tumors in mice fed LFD (Figure 3A). On the other hand, consistent with the increased proportion of epithelial tumors, BP-3 was promotional for epithelial tumorigenesis in mice fed LFD-HFD (Figure 3C), while reducing spindle cell tumorigenesis (Figure 3D).” 

Researchers saw that BP-3 treatment increased the number of lesions only in mice fed the HFD-LFD. Proliferation in all dietary groups was increased by BP-3 treatment. An analysis of variance (ANOVA) test found that BP-3 treatment only produced a significant effect on proliferation in the mammary glands of 26-week old mice.

“We observed a modest, but statistically significant, reduction in estrogen levels by BP-3 treatment of mice fed HFD-LFD.”

Importantly, the researchers note that, in this study and others, they observed a “pubertal window of susceptibility,” reinforcing that puberty is a highly sensitive window of time for adverse exposures. Ultimately, the team also found that BP-3 enhances estrogen-stimulated mammary gland proliferation in pubertal mice fed a HFD.

“Benzophenone-3 was protective for epithelial tumorigenesis in mice fed lifelong low-fat diet, while promotional for epithelial tumorigenesis in mice fed adult high-fat diet.”

Conclusion

Collectively, the researchers’ findings suggest that exposure to BP-3 may have adverse consequences in mammary tumorigenesis.

“Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology.”

“This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.”

“Regarding BP-3, it will be valuable to eventually explore pubertal versus adult exposure to BP-3 on a constant diet regimen.”

“Nonetheless, BP-3 treatment clearly shows differential effects between the three dietary regimens.”

Click here to read the full scientific study, published in Oncotarget.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.