Dexamethasone treatments for cancer may enhance the effectiveness of the chemotherapy


A common drug used to alleviate side effects of cancer treatment may also make the treatment more successful if given beforehand, report a consortium of research institutions including the University of Connecticut.

Dexamethasone, a steroid often given to decrease swelling and nausea, and relieve side effects of chemotherapy treatments for cancer, may also enhance the effectiveness of the chemotherapy itself, the researchers reported in ACS Nano.

Cancerous tumors tend to grow abnormal blood vessels.

Squished, twisted, and compressed, these blood vessels inside tumors also tend to be leaky.

“This creates low pressure in the blood vessel, while the tumor tissue has high pressure.

And you can’t flow from low to high pressure,” says Matthew Stuber, UConn assistant professor of chemical and biological engineering, and study author.

Common steroid could soften up tumors for chemo
Leaky Blood Vessels. Two conceptual images of a cancer tumor blood vessel. In (A), the right side of the blood vessel (marked by the dark gray bar below the pore) is leaky, with a large pore that allows too much fluid to leave the vessel. The left side shows the same blood vessel after dexamethasone treatment; the pore is smaller and the vessel less leaky. Dexamethasone treatment does the same thing to the vessel pores in (B). The smaller pores allow more anti-cancer drug (green dots) to travel further inside the tumor, leading to more effective treatment. Credit: John Martin, University of Tokyo, and Matthew Stuber, UConn

The low pressure in the blood vessels makes it hard for the chemotherapy drugs to penetrate the interior of the tumor.

The most important factors determining how far the chemotherapy drugs get inside the tumor are the fluid pressure inside the blood vessels, and the pressure of the tumor tissue itself.

Stuber and his colleagues did the math, and figured out how much the pressures would have to change relative to each other for the chemotherapy to destroy more of the tumor.

Stuber and his lab, the Process Systems and Operations Research Laboratory, applied data from their co-author’s experiments to an established computer model of how fluid and molecules flow through a tumor.

The data they used for the model came from videos taken through microscopes that showed how chemotherapy penetrated tumors.

These pictures showed that most of the chemotherapy attacked the outer edges of the tumor. Very little made it deep inside.

Dexamethasone does two things that could ensure the chemotherapy drugs reach their target.

First, the steroid shrinks the pores that allow drugs and other molecules to pass through the walls of blood vessels.

This makes the blood vessel less leaky, raising the pressure.

Second, dexamethasone tends to soften the protein scaffolding that holds cells together into tissues.

This makes the tumor tissue expand and lowers the pressure, making it easier for fluid and drugs to penetrate.

When dexamethasone is added at the right dosage, there is a dramatic improvement, according to the mathematical model Stuber’s lab ran.

“Fluid flows into the tissue better,” the researchers say.

And that is what their collaborators at the University of Tokyo and the University of Cyprus found when they tested the drug on breast cancer in animal models.

The timing and dosage of the dexamethasone treatment needs more testing to show how it would be most effective in humans, the researchers note.

Stuber also cautions that there are some risks.

For instance, improving blood flow through the tumor allows it to take up nutrients and grow more effectively, which is a bad thing.

And too much dexamethasone can tighten the pores in the blood vessels too much, preventing the chemotherapy drugs from entering the tumor.

But his lab is working on identifying the right balance.

They are already thinking about how to fine-tune the mathematical models for individual patients and cancers, figuring out when and how much dexamethasone to give.

Ideally, says Stuber, researchers want to be able to determine, “if we give this much treatment, this is how we expect the tumor to be affected.”

Cancer still a severe threat to the health of human is beings.

The WHO recent report shows that cancer has become the second leading cause of death worldwide, almost 1 in 6 deaths are due to cancer in 2015 (World Health Organization [WHO], 2018).

It is estimated that the new cases of cancer patients will rise rapidly in recent years, the morbidity is expected to reach approximately 24 million in 2035 (Huang, 2006).

Not only does cancer bring serious pains to patients, lower their life quality, and also carries a significant economic burden to their families and governments

Therefore, cancer has been a severe public health problem worldwide.

Chemotherapy is one of the commonest therapeutic modalities in the management of cancer.

However, the drugs currently used in the chemotherapy only have a limited success with severe side-effects, including myelosuppression, gastrointestinal toxicity, cardiotoxicity, hepatotoxicity, neurotoxicity, ototoxicity, etc.

And then these serious side-effects make many patients discontinue the chemotherapy (Zhou et al., 2011Salehi et al., 2014Irving et al., 2015).

Thus, there is a need to explore effective adjuvant strategies to prevent and reduce the chemotherapy-induced side effects.

Naturally occurring products as adjuvant therapy have been shown a promising potential in preventing the chemotherapy-induced side effects (Palipoch et al., 2014).

Curcumin (C21H20O6) (Figure ​(Figure1)1) is an active compound from natural plant Curcuma longa L., which is widely used as a coloring and flavoring agent in food industry and a herbal medicine in Asian countries for thousands of years to treat vomiting, headache, diarrhea, etc.

Recently, pharmacological studies have revealed that curcumin has strong antioxidative, anti-microbial, anti-inflammatory and anticancer activities (Bishnoi et al., 2011Wang et al., 2011a,b2012Shiau et al., 2012Mendonça et al., 2013Sankrityayan and Majumdar, 2016Dai et al., 2018).

Growing evidence shows that curcumin is a very safe product to human being (Shehzad et al., 2013).

It can not only prevent carcinogenesis and enhance clinical efficacy of chemotherapy through sensitizing cancer cells to the commonly used chemotherapy, and also protect normal cells from chemotherapy-induced damages (Zhou et al., 2011Mendonça et al., 2013).

In the present article, we review the preventive effect of curcumin against chemotherapy-induced myelosuppression, gastrointestinal toxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, neurotoxicity, ototoxicity and genotoxicity, and discuss its action mechanisms.

Our aim is to provide some reference information for researchers and scientists in basic and clinical settings.

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Curcumin formula.

Curcumin Ameliorates Chemotherapy-Induced Gastrointestinal Toxicity

Gastrointestinal toxicity is one of the commonest chemotherapy-induced side-effects.

The patients receiving chemotherapy almost suffer from vomiting, diarrhea, nausea and anorexia (Yao et al., 2013).

A reported study showed that a third of patients receiving chemotherapeutic agent 5-FU have life-threatening diarrhea because 5-FU-induced gastrointestinal toxicity (Irving et al., 2015).

Mucosal barrier injury, including an increased villous atrophy and elevated intestinal permeability in gastrointestinal tract, is an important adverse effect of anticancer drugs. van’t Land et al. (2004) found that the absorption surface of the duodenum were remarkably decreased to 38 ± 6% on day 3, and the absorption surface of jejunum further reduced on day 4 after chemotherapy.

In the meantime, they also observed methotrexate (MTX)-induced intestinal damage with marked increase of MPO+ cell influx in the duodenum and the jejunum.

Interestingly, in the animals pretreated with curcumin at 2.5 mg/kg starting 24 h prior to the first MTX administration, the authors observed a remarkable re-establishment of villous structure without weight loss and marked increase of MPO+ cell influx (van’t Land et al., 2004). Yao et al. (2013) also reported that curcumin could improve 5-FU-induced diarrhea, decease 5-FU-associated weight loss, attenuate 5-FU-induced mucosa atrophy and villi loss, and reverse 5-FU-induced dramatic increase of serum endotoxin D-lactate and D-amino-acid oxidase (DAO) (Wang et al., 2011b).

These findings demonstrate that curcumin has protective effect on chemotherapy-induced intestinal dysfunction and mucosa morphology.

Curcumin Reduces Chemotherapy-Induced Cardiotoxicity

Cardiotoxicity is a dose-limiting factor affecting the clinical outcome of chemotherapy.

Growing evidence shows that chemotherapy-induced cardiotoxicity involves oxidative stress, mitochondrial damage, calcium flux alteration and activation of proapoptotic signaling cascades, etc. (Dayton et al., 2011).

Doxorubicin (DOX) is a common drug used in the management of malignancies, however, the lethal cardiac side-effect limits the therapeutic efficacy of DOX, and even some patients have to discontinue the DOX therapy (Swamy et al., 2012).

Swamy AV reported that repeated use of Dox (15 mg/kg) for 2 weeks induced cardiotoxicity with elevated cardiac toxicity markers serum creatine kinase (CK) and lactate dehydrogenase (LDH), and decreased antioxidant enzyme [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GTP) activities].

Curcumin (200 mg/kg, po) was then used as pretreatment for 2 weeks and for another 2 weeks in combination with Dox.

The results showed that curcumin administration remarkably reduced the elevated level of cardiac toxicity markers and protected myocardium from Dox damage (Swamy et al., 2012). Benzer et al. (2018) found that DOX-treated rats produced the elevated CK and LDH, and decreased SOD, CAT and GTP activities.

Curcumin administration via oral routine (100 or 200 mg/kg body weight) for 7 days could significantly lowered serum CK and LDH, and enhanced the SOD, CAT, GTP activities (Benzer et al., 2018). Sheu et al. (2015) reported that pretreatment of curcumin (30 μM) increased the antioxidant ability of normal cells and attenuated DOX-associated cardiotoxicity.

Venkatesan N revealed that administration of curcumin (200 mg/kg) could significantly attenuate the early manifestation of adriamycin (ADR)-induced cardiotoxicity such as ST segment elevation and an increase in heart rate, and prevent the elevation in ADR-induced serum CK and LDH (Venkatesan, 1998). Bahadir et al. (2018) found that cisplatin caused severe myocardial degenerative alterations, a remarkable increase in malondialdehyde (MDA) level and significant decrease in CAT and SOD activities. However, the cisplatin-induced cardiotoxic manifestations markedly improved by the pretreatment of curcumin (Bahadir et al., 2018). The above evidence demonstrates that curcumin has protective activity against chemotherapy-induced cardiotoxicity.

Curcumin Prevents Chemotherapy-Induced Hepatotoxicity

Hepatotoxicity is a well-described side effect of chemotherapy and is also a major limitation to its clinical application. Palipoch et al. (2014) found that cisplatin could significantly reduce hepatic SOD and CAT activities, and increase hepatic MDA levels and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.

Histopathological observation showed that cisplatin induced remarkable hepatocytic damages such as liver congestion and ground glass changes.

Pretreatment with curcumin and/or α-tocopherol could improve cisplatin-induced damages to hepatic enzymes and histopathology (Palipoch et al., 2014). Mohamad et al. (2009) reported that a single dose of DOX (7.5 mg/kg) could induce hepatotoxicity with serum ALT and AST elevations.

The pretreatment of Curcuma longa L. extract could significantly restore the ALT and AST level, and prevent hepatotoxicity from DOX. Fetoni et al. (2014) found that the dose of 200 mg/kg curcumin not only has no toxic effects on the treated animal liver, and also attenuate DOX-induced hepatotoxicity. 

Waseem et al. (2017) revealed that oxaliplatin (200 μg/mL), a platinum-based chemotherapeutic agent, significantly increased lipid peroxidation (LPO) levels and protein carbonyl (PC) contents, and reduced the levels of glutathione (GSH) and non-protein thiol (NP-SH) in the isolated rat liver mitochondria.

Oxaliplatin was also found to lower antioxidant and respiratory chain enzymes activities in mitochondria.

The pretreatment of curcumin (5 μM) markedly restored the levels of LPO, GSH, NP-SH, and PC contents, and antioxidant and mitochondrial respiratory chain enzymes activities (Waseem et al., 2017).

They also found that pretreatment of curcumin prior to cisplatin could prevent cisplatin-induced hepatotoxicity in rat model (Waseem et al., 2014). Wang et al. (2014) investigated the effect of curcumin on cisplatin-induced hepatotoxicity and ultrastructural damage.

Their results showed that cisplatin had significant liver damage with vacuolated cytoplasm and blurred trabecular structure after cisplatin (50 mg/kg/day) was injected via i.p to Kunming mice for 10 days, and curcumin treatment (200 mg/kg/day) for 10 days could prevent cisplatin-induced liver damage (Wang et al., 2014). 

Hemeida and Mohafez (2008) found that a single dose of MTX (20 mg/kg I.P.) was able to induced hepatotoxicity with mild inflammation and necrosis in hepatocytes and sinusoidal cells as well as decreased liver SOD and CAT activities, and increased MDA level. Curcumin treatment (100 mg/kg, I.P.) once daily for 5 days after MTX injection restored liver SOD and CAT activities, and MDA level, and ameliorated MTX-induced liver damage (Hemeida and Mohafez, 2008).

Curcumin Ameliorates Chemotherapy-Induced Nephrotoxicity

Nephrotoxicity is a severe chemotherapy-associated side-effect.

Chemotherapy often causes kidney injury through damaging renal structure and function (Zhou et al., 2011).

For example, cisplatin increases the levels of creatinine (Cr) and BUN, and causes directly swelling of proximal tubular cells with cytoplasmic vacuolization and necrosis (Ortega-Domínguez et al., 2017). Ortega-Domínguez et al. (2017) found that cisplatin-associated nephrotoxicity could be prevented by curcumin treatment.

The kidney in the combined treatment group with curcumin and cisplatin showed minimal cytoplasmic vacuolization without necrosis, and animals treated by curcumin showed no histological abnormality in the kidney.

Transmission electronic microscopy showed that cisplatin-induced extensive mitochondrial abnormalities, including mitochondrial swelling and rupture of cristae, were significantly attenuated by curcumin treatment (Ortega-Domínguez et al., 2017).

Experimental results from Zhou et al. (2011) showed that chemotherapeutic drug mitomycin (MMC) dose-dependently increased the levels of Cr and BUN in mice, suggesting that MMC induced severe damage to the kidney.

After administration of curcumin the levels of Cr and BUN were brought back to those of the control.

The abnormalities were less evident in the combined group of curcumin and cisplatin treatment, clearly indicating an efficient activity of curcumin in the prevention of these mitochondrial abnormalities (Zhou et al., 2011).

Their results further confirm that curcumin reduce chemotherapy-associated nephrotoxicity.

Curcumin Decreases Chemotherapy-Induced Ototoxicity

Ototoxicity is an unwanted side-effect seen in cancer patients received chemotherapy, especially, platinum-based chemotherapeutic agents.

After platinum-based chemotherapy such as cisplatin treatment, approximately 60 to 80% of the patients suffer from bilateral, symmetric middle- or high-frequency hearing loss, which affects patients’ communication and impairs their quality of life (Salehi et al., 2014). Growing evidence shows that the increase of reactive oxygen species (ROS) is an important cause of cisplatin-induced ototoxicity.

The use of antioxidants to balance the redox condition is a major strategy to protect or rescue the auditory function from cisplatin-induced ototoxicity.

Curcumin as a common antioxidant agent was stands out as an important component to ameliorate chemotherapy-induced ototoxicity (Fetoni et al., 2014). Fetoni et al. (2014) found that cisplatin significantly enhanced lipid peroxidation expression in outer hair cells (OHC) and induced the OHC loss.

And the use of curcumin (200 mg/kg) remarkably reduced lipid peroxidation expression and the OHC loss.

This preclinical study showed that curcumin (200 mg/kg) treatment reduced hear loss of about 20 dB in the threshold compared to cisplatin treatment, indicating that curcumin ameliorated the onset of cisplatin-induced ototoxicity (Fetoni et al., 2014).

 Salehi et al. (2014) also found that cisplatin treatment could lead to an average hearing loss of 50 dB and a curcumin and dexamethasone-loaded nanoparticle could attenuate cisplatin-induced hearing loss across all of the hearing frequencies.

Curcumin Attenuates Chemotherapy-Induced Myelosuppression

Chemotherapeutic agents frequently damage bone borrow cells, subsequently causing myelosuppression, which increases susceptibility to microbial infection.

Chemotherapeutic agent Etoposide treatment (50 mg/kg b.w., intraperitoneally) for 3 days caused serious hypoplasia of bone marrow. And then curcumin (100 and 200 mg/kg b.w.) was administrated to the Etoposide-treated rats via gavage for 7 days.

The results showed that curcumin improved significantly etoposide-induced the percentage of granulocytic precursors and lymphocytes, demonstrating that curcumin has a remarkable activity in attenuating chemotherapy-associated myelosuppression (Papiez, 2013).

Recently, Chen et al. (2017) found in a tumor-bearing animal that curcumin could improve tumor-associated anemia and survival rate of chemotherapeutic carboplatin-treated mice. Histologic study showed a significant improvement in the myelosuppression of chemotherapy-treated mice (Chen et al., 2017).

Curcumin Attenuates Chemotherapy-Induced Neurotoxicity

Neurotoxicity is also a common adverse effect of chemotherapy.

Among chemotherapy-induced neurotoxicities, peripheral neuropathy is the commonest one. Actually, after a full course of cisplatin therapy, patients often suffer from severe sensory peripheral neuropathies with extreme pain and low life quality (Mendonça et al., 2013).

Curcumin was proved to possess protective action on neuronal cell lines and neuronal tissues.

In clinical settings, curcumin is used as a neuroprotective agent in the management of epilepsy, Alzheimers’ disease, and other neurodegenerative disorders (Mendonça et al., 2013). Bishnoi et al. (2011) reported that curcumin had a protective action on haloperidol-associated neurotoxicity.

Pretreatment of curcumin could dose-dependently prevent the chronic haloperidol-induced behavioral, cellular, and neurochemical changes (Bishnoi et al., 2011). Dai et al. (2018) found that curcumin could reduce colistin-induced neurotoxicity in N2a cells. Curcumin was also found to reduce the histological changes of the dorsal root ganglia (DRG) and sciatic nerve in the animal model of sciatic nerve crush.

For example, curcumin treatment could attenuate the decrease of total number, diameter, and area of the damaged sciatic nerve fibers (Bishnoi et al., 2011).

To reduce chemotherapy-induced neurotoxicity, Mendonça et al. (2013) used curcumin in their study for investigating its effect on cisplatin-induced neurotoxicity in NGF-differentiated PC12 cells.

The results showed that 1.0 ug/ml of curcumin had no effect on cisplatin-induced neurite outgrowth, however, 10 ug/ml of curcumin could significantly decrease cisplatin-induced inhibition of neurite outgrowth by up to 50%. They also found in Wistar rats that curcumin could reduce cisplatin-induced degeneration of nerve fiber of the sciatic nerve (Mendonça et al., 2013).

Curcumin Prevents Chemotherapy-Induced Genotoxicity

Growing studies also show that chemotherapy could cause genotoxicity, which might induce secondary cancer (Said Salem et al., 2017).

In the Said Salem et al. (2017) study, a single dose of either cisplatin (6.5 mg/kg) or methotrexate (10 mg/kg) was injected intraperitoneally to mice.

Kidney and bone marrow cells obtained from cisplatin- or methotrexate-treated mice was employed to measure DNA damage using a Comet assay, and bone marrow cells also used to measure chromosome damage using a micronucleus assay.

Their results showed that cisplatin or MTX alone treatment significant increased the percentage of micronucleated polychromatic erythrocytes (MNPCEs) and DNA strand breaks (DNA damage) of kidney and bone marrow cells.

The oral administration of curcumin at the dosage of 60, 90, or 120 mg/kg for three consecutive days before either cisplatin or methotrexate treatment significantly decreased the incidence of cisplatin- and methotrexate-induced micronuclei and DNA damage (Said Salem et al., 2017). Chen et al. (2017) used a probe derived from curcumin to investigate the effect of curcumin on DNA repair pathway in mice bone marrow cells. The results showed that curcumin could attenuate carboplatin-induced DNA damage through initiating DNA repair pathway (Chen et al., 2017).

More information: John D. Martin et al. Dexamethasone Increases Cisplatin-Loaded Nanocarrier Delivery and Efficacy in Metastatic Breast Cancer by Normalizing the Tumor Microenvironment, ACS Nano (2019). DOI: 10.1021/acsnano.8b07865

Journal information: ACS Nano
Provided by University of Connecticut


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