Open access peer-reviewed chapter

Attenuating Cancer Cachexia-Prolonging Life

Written By

Charles Lambert

Submitted: 21 September 2021 Reviewed: 15 October 2021 Published: 27 November 2021

DOI: 10.5772/intechopen.101250

From the Edited Volume

Frailty and Sarcopenia - Recent Evidence and New Perspectives

Edited by Grazia D’Onofrio and Julianna Cseri

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Abstract

Death by cancer cachexia is dependent on the time allotted to cancer to cause muscle and fat wasting. If clinicians, nurses, researchers can prolong the life of a cancer patient other therapeutic interventions such as radiation and chemotherapy may be given the time to work and rid the cancer patient of tumors and save lives. Three areas by which cancer induces cachexia is through impaired insulin-like growth factor signaling, elevations in the proinflammatory cytokines TNF-α and IL-6 and subsequent reductions in muscle protein synthesis and increases in muscle protein degradation. Therefore, it is important to augment the IGF-1 signaling, block TNF-α and IL-6 in cancer cachexia and in other ways augment muscle protein synthesis or decrease muscle protein degradation. Ghrelin like growth hormone secretagogues, monoclonal antibodies to TNF-α and IL-6, testosterone, and anabolic steroids, the beta 2 agonist albuterol, resistance exercise, and creatine monohydrate (with resistance exercise) are beneficial in increasing muscle protein synthesis and/or reducing muscle protein breakdown. With these muscle augmenting agents/interventions, the duration that a cancer patient lives is prolonged so that radiation and chemotherapy as well as emerging technologies can rid the cancer patient of cancer and save lives.

Keywords

  • muscle wasting
  • anabolism
  • oncology
  • nutrition
  • exercise
  • pharmacotherapy

1. Introduction

There are no drugs approved to treat cancer cachexia in the US. This is unfortunate and a flaw, I believe, in the FDAs criteria for cancer cachexia drug approval in the United States [1]. Their criterion measure has been an improvement in function. This variable depends on the nervous system in addition to skeletal muscle because they are functional in nature. Cachexia, by definition is the loss of skeletal muscle and adipose tissue. Drugs designed to affect skeletal muscle have little and probably no effect on the nervous system. As such, the FDA should remove the functional requirement or make functional training along with drug administration a requirement in phase I, II and III studies. As it is, all drugs anabolic to skeletal muscle will likely fail a functional test since they have no effect, without functional exercise, on the nervous system.

With this short coming of the approval process in mind, other measures must be taken to attenuate cachexia with the intent of allowing more time for chemotherapeutic agents and radiation therapy to exert their tumor killing activity. It is indeed a matter of time for cachectic cancer patients; the more time they have, the better the outcome with the goal to be to cure cancer for those individuals suffering from cancer cachexia and save lives. Off-label use of drugs that are approved for other conditions would appear to be a very important action to take for clinicians to this end. For example, the use of monoclonal antibodies for IL-6 and TNF-α which are approved for other indications would appear beneficial in treating many cancers as these proinflammatory cytokines are secreted during cancer-inflammation mediated by these cytokines wreaks havoc on the patient. In addition, IL-6 and TNF-α are directly related to muscle catabolism in models of cancer cachexia [2, 3]. Hypermetabolism is another manifestation of cancer cachexia [4]. Drugs that block the action of epinephrine (a catecholamine) would act to reduce metabolic rate and slow the rate of muscle wasting [5]. The drug propranolol blocks both beta 1 and beta 2 receptors metabolic rate. This is just one example of a drug that could reduce hypermetabolism of cachexia. A third factor, although taboo especially in the sporting world, is the use of anabolic agents to stimulate muscle protein synthesis [6, 7, 8] in the face of reduced muscle protein synthesis, and elevated muscle protein breakdown. Thus, the off-label use of anabolic steroids, testosterone, and growth hormone secretagogues should be explored although some these agents are not FDA approved. For example, anamorelin was found to be safe and effective in increasing lean body mass through phase III trials but did not increase grip strength [9].

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2. Mechanisms of IL-6 induced muscle catabolism

In one study, to date, IL-6 has been shown to reduce basal and eccentric exercise induced protein synthesis by generally well accepted mechanisms [10].

One mechanism by which IL-6 decreases muscle mass is by activating the STAT 3 pathway which causes muscle protein breakdown to acute phase proteins. An acute phase protein derived from skeletal muscle that is synthesized upon IL-6 binding in skeletal muscle and activation of the STAT 3 pathway is fibrinogen. This was reported in an experimental animal model of cancer cachexia [2]. In a subsequent study this group also reported that blocking the JAK/STAT 3 pathway inhibited skeletal muscle wasting [3]. Therefore, this is a way that IL-6 induces muscle protein breakdown also known as proteolysis.

Another mechanism described in the literature [11] is autophagy where the cells in essence eat themselves. This would be considered a second mechanism by which proteolysis is induced by IL-6.

A third mechanism by which IL-6 can induce protein breakdown is by activation of atrogin 1 (MAFBX) [12].

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3. Mechanisms of TNF-α induced muscle catabolism

In a pre-clinical proof of concept study Lang et al. [13] reported that a TNF-α infusion to rats reduced the muscle protein synthesis rate (decreased by 39%) by way of reducing the mRNA to protein conversion (decreased by 39%) of both myofibrillar and sarcoplasmic proteins in the gastrocnemius muscle. The plasma TNF-α concentration was raised to 500 pg/ml in this study.

A question that remains is: is it the plasma concentration of the TNF-α that is important and/or the muscle derived TNF-α [14] that is important in the regulation of muscle protein synthesis. A similar example in skeletal muscle are the acute phase proteins which are derived from muscle such as fibrinogen.

On the muscle protein breakdown side of the muscle mass equation, Li et al. [15] reported that TNF-α utilizes the p38 MAPK pathway to cause expression of atrogin-1/MAFBX in skeletal muscle. This activation of atrogin-1/MAFBX activates the ubiquitin-proteasome pathway for muscle protein degradation. This was confirmed when inhibitors of p38 inhibited ubiquitin conjugation activity.

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4. Impairment of the IGF-1 pathway in muscle catabolism

Endogenous insulin-like growth factor-1 (IGF-1) is a very potent anabolic agent in the human body. IGF-1 is released from the liver after growth hormone (GH) stimulation of liver cells. Another form of IGF-1 (a splice variant) mechano-growth factor (MGF) is produced by the mechanical loading of skeletal muscle [16] and is released in a paracrine/autocrine fashion and is also a potent anabolic agent. Lambert et al. [14] reported that the combination of chronic aerobic and resistance exercise training in humans, resulted in an upregulation in MGF mRNA in skeletal muscle.

The mechanism of action of IGF-1 in causing muscle protein synthesis is through PI3K/AKT/mTOR signaling [17]. This would also be the pathway via a common receptor by which insulin stimulates muscle protein synthesis. Interestingly, lack of basal IGF-1 signaling resulted in activation of atrogin-1 and Murf-1, two factors that induce muscle protein breakdown through the ubiquitin-proteasome pathway [17, 18]. Additionally, these authors [18] reported when basal IGF-1 levels were absent there was an activation of GSK-3B which phosphorylates and inactivates 4EBP1-a translation (protein synthesis) initiation factor. This activation of muscle protein breakdown through these two mediators resulted in myosin heavy chain 1 and 3 degradation in an animal model. In addition to causing muscle protein synthesis, IGF-1 acts to reduce muscle protein breakdown through reducing atrogin-1 and Murf-1.

In a thorough study on the effects of cancer cachexia on the IGF-1 system in skeletal muscle and plasma, Costelli et al. [19] reported that there was about a 50% reduction in muscle IGF-1 and plasma levels were also reduced. The model they used for cancer cachexia was the Yoshida AH-130 hepatoma model [19].

To summarize, IGF-1 is a potent stimulator of anabolism or muscle growth and impairing the signaling of IGF-1 results in reduced muscle protein synthesis through the PI3K/AKT/mTOR pathway as well as increased muscle protein degradation through an increase in atrogin-1 and Murf-1. Additionally, GSK-3B is activated which inhibits translation initiation by phosphorylating 4EBP-1 when IGF-1 signaling is impaired.

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5. Treatment of cachexia

5.1 Resistance exercise training

Weight training or more commonly known as resistance exercise training in which an individual contracts his muscles against the force of a weight stack, free weights, or sometimes resistance bands is a way in which to increase muscle protein synthesis [20]. This bodes well for the cancer patient if they have the functional ability to undergo these types of workouts. It is well known that this increase in protein synthesis chronically will result in an increase in muscle mass. An additional benefit of exercise and likely a precursor to muscle growth is a decrease in intramuscular proinflammatory cytokine mRNAs and an increase in mechano-growth factor mRNA which is a slice variant of IGF-1.

5.2 Creatine monohydrate

An adjunct nutritional supplement to resistance training is creatine (monohydrate). Creatine when ingested in sufficient quantities, for example, 20 g/day for 5 days will elevate the intramuscular stores of creatine. This elevation of intramuscular creatine can increase the rate of phosphocreatine resynthesis in man [21]. This is by way of the reaction ATP + creatine yields PCr + ADP. Where ATP is adenosine triphosphate, PCr is phosphocreatine, and ADP is adenosine triphosphate. Creatine ingestion in the manner described above improves not only PCr resynthesis but also exercise capacity [22].

5.3 Ibuprofen and acetaminophen

It is well known that a bout of resistance training will increase muscle protein synthesis in the hours after exercise [20]. Resistance exercise also increases the muscle protein degradative cytokines IL-6 and murf-1 mRNA [23]. Resistance exercise with ibuprofen or acetaminophen ingestion blunts the IL-6 and murf-1 response to resistance exercise [23]. Cancer cachexia increases IL-6 and murf-1 leading to more protein degradation [10]. Therefore resistance exercise with acetaminophen or ibuprofen is beneficial for increasing muscle protein synthesis and decreasing muscle protein breakdown to achieve a more favorable response (increasing synthesis and decreasing breakdown = more + net protein balance; Trappe et al. [23]). This would improve the ability to accrete more muscle mass in the face of cancer cachexia. It is suggested that future clinical trials combine resistance training with acetaminophen or ibuprofen at the maximal daily dosage in cachectic cancer patients. For detailed schematic on how these analgesic agents affect protein metabolism see Trappe et al. [23].

5.4 Albuterol

In humans, Uc et al. [24] found that administration of the beta-2 agonist albuterol increased thigh cross-sectional area by 5.3% and whole-body fat free mass by 9.5% in Parkinson’s patients over 14 weeks (16 mg/day). Unpublished data suggests that muscle protein synthesis is elevated by ~90% in elderly individuals with 16 mg/day over 10 days of albuterol administration (Lambert et al. unpublished observations). Albuterol would appear to be an anabolic agent that should be administered off label in cancer cachexia in clinical trials.

5.5 Anamorelin and ibutamorelin

Anamorelin is active orally, centrally penetrant, and selective agonist of the ghrelin/growth hormone secretagogue receptor-1a and was under development for the treatment of cancer cachexia and anorexia [25] (Drug Bank). It increases growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein (IGFBP-3) and apparently has no side effects as testosterone administration does. It also stimulates appetite [9]. It has been shown in Phase III Clinical Trials to increase appetite, body weight, lean body mass, but not muscle strength as measured by hand grip strength [9]. The natural agonist for ghrelin/growth hormone secretagogue receptor-1a, ghrelin has a short half-life, however; anamorelin has better pharmacokinetic properties as evidenced by a more sustained delivery [26]. It is a dipepetide of molecular weight 546.716 (Drug Bank). Apparently, this drug failed in Phase III Clinical Trials due to lack of an effect on grip strength although it increased lean body mass [9]. The only side effect noted with anamorelin was a small risk of headache [26]. Anamorelin is approved for clinical use in Japan but not the US or Europe.

Ibutamorelin, like anamorelin, is another ghrelin analogue that stimulates growth hormone secretion from the pituitary and IGF-1 secretion from the liver. Svenson et al. reported that 2 months of treatment of individuals 18–50 years old with 25 mg of ibutamorelin resulted in and increase in growth hormone and IGF-1 and a significant increase in fat free mass when measured by DEXA or by a four compartment model. Basal metabolic rate was elevated at 2 weeks but not at 8 weeks. Nass et al. [27] reported that in individuals 60–81 years of age, 25 mg of ibutamorelin administered over 2 years resulted in a loss of 0.5 kg of fat free mass in placebo group but a gain of 1.1 kg in the ibutamorelin group. This was accompanied by an increase in growth hormone and IGF-1 and a reduction in LDL cholesterol of 0.14 mmol/L. Murphy et al. (1998) reported that in individuals 24–39 years of age, ibutamorelin (25 mg/day) accompanied by a 18 kcal/kg/day energy intake for 2, 14 day periods resulted in a + 2.69 nitrogen balance for the ibutamorelin group but a −8.97 for the placebo group during the last 7 days of the second 14 days, which suggests that this anabolic agent would be preventative of muscle loss with a very low energy intake. Unfortunately, ibutamorelin did not show efficacy in functional tests which are the criteria the FDA uses for cancer cachexia drugs [1] and in other conditions which induce muscle loss such as hip fracture [28]. Both anamorelin and ibutamorelin did not show functional efficacy in clinical trials. Why functional capacity improvement would be the ultimate criteria for cancer cachexia would be beyond me. Since the problem in cancer cachexia would be considered muscle wasting and not a functional problem [1]. Maybe it is time for the FDA to change their criteria for approval of safe and effective drugs which cause anabolism and prevent catabolism during cancer cachexia. Because of the FDAs short sightedness, both of these drugs (anamorelin and ibutamorelin) have been rendered the status of nutritional supplements.

5.6 Megace

Megestrol acetate (Megace) stimulates appetite, increases feeding behavior, alone-reduces lean body mass-but in combination with testosterone therapy and resistance exercise training, increases lean body mass in underweight elderly men [29]. This combination of Megace, testosterone, and resistance training may be beneficial in cancer patients. Megace alone decreased muscle mass but when combined with testosterone AND exercise resulted in a substantial increase in muscle mass in 12 weeks of training and administration [29]. It was hypothesized by the authors that Megace binds to the androgen receptor and blocks the action of testosterone. However, when combined with resistance exercise and testosterone replacement (100 mg/week) resulted in substantial muscle growth (hypertrophy). Therefore, resistance exercise, in some way acts, permissively to allows underweight elderly men to maintain muscle mass when testosterone is low and in the face of testosterone replacement to increase muscle mass. Likely, this is through the androgen receptor.

5.7 Testosterone and anabolic steroids

Testosterone and anabolic steroids are anabolic to skeletal muscle [30]. Bhasin et al. [30] illustrated the fact that testosterone is anabolic to skeletal muscle in stepwise fashion with increasing dosage. The correlation between log testosterone and lean body mass (a surrogate for muscle mass) was 0.73, a very strong correlation. Urban et al. [6] reported that the mechanism of action of testosterone, with regard to, skeletal muscle anabolism in elderly individuals with low testosterone (testosterone < 480 ng/dL), was an increase in muscle protein synthesis which appear by elevated muscle IGF-1 concentrations and to be mediated by an elevation of IGF-1 in skeletal muscle. Cancer patients in general are hypogonadal (testosterone concentrations less than 300 ng/dL; Burney et al. [31]). Therefore, the administration of testosterone or its much less androgenic (secondary side effects) analogue anabolic steroids would appear to be a logical step in the treatment of cancer cachexia which may at least partly be due to low testosterone concentrations. The only caveat is that cancers that are hormone sensitive may not be a good candidate for testosterone or anabolic steroid therapy due to possible proliferation of the tumor. Nandrolone decanoate, an intramuscular injectable anabolic steroid and oxandrolone, an oral anabolic steroid are very low in secondary side effects because of their low androgenic to anabolic ratio. They have been used in other disease populations such as HIV [7] for oxandrolone and nandrolone decanoate [8]. Thus, the utility of these drugs along with testosterone in cancer would appear unquestionable. Clinical trials using these anabolic agents in an off label fashion in multiple types of cancer is warranted.

5.8 Monoclonal antibodies

A logical step in decreasing the cachexia associated with cancer would be neutralizing circulating IL-6 and TNF-α with monoclonal antibodies.

There are many monoclonal antibodies to TNF-α FDA approved for other uses. To the best of my knowledge, there are one or a few monoclonal antibodies to IL-6 for different indications than cancer. Clearly, as discussed in a recent letter to the editor [5], this would be a very important application of monoclonal antibody technology.

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6. Conclusion

Inflammation through IL-6 and TNF-α is an important mechanism by which cancer causes muscle catabolism. Reducing inflammation by exercise, non-steroidal anti-inflammatory drugs, and monoclonal antibodies would appear to be a potential strategy to curtail cancer cachexia. Also, augmenting protein synthesis by utilizing exercise, creatine monohydrate, albuterol, testosterone, and anabolic steroids would also appear to be a potential strategy to curtail cancer cachexia. Utilizing megestrol acetate would be indicated for cancer cachexia only if accompanied by testosterone replacement and exercise. The off-label oral use of albuterol is anabolic to skeletal muscle in healthy elderly individuals and future clinical trials could evaluate its utility in cancer cachexia. Ghrelin analogues, that is, growth hormone secretagogues, although not FDA approved, elevate, in pulsatile manner, growth hormone and IGF-1 concentrations and increase significantly lean body mass accrual (some studies in cancer) with few if any side effects. Therefore, these nutritional supplements are indicated for the treatment of cancer cachexia. For a depiction of Ligand-Receptor interactions discussed in this Chapter please see (Figure 1).

Figure 1.

A schematic representation of monoclonal antibodies and cytokines, mechanism of action of growth hormone and putative mechanism of beta-2 agonists in animals, and of testosterone and anabolic steroids on skeletal muscle.

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Written By

Charles Lambert

Submitted: 21 September 2021 Reviewed: 15 October 2021 Published: 27 November 2021