Page 82 - ITPS-8-1

INNOSC Theranostics and
Pharmacological Sciences Anabolic agents in cancer cachexia

as strength measurements, which take time and are not are explained by the Michaelis–Menten kinetics associated
routinely conducted by oncology teams. with androgen/receptor interactions, such as the substrate
Approximately 80% of all cancer mortalities are concentration that causes 1 - half maximum reaction
associated with highly cachectic cancers, such as pancreatic velocity (K ) and maximal reaction velocity (V max ). K is
m
m
and non-small cell lung carcinoma. The prevalence of derived from the middle of a hyperbolic curve, in which
cachexia is greater in males, those with a lower body mass the concentration at 50% V max elicits a linear response but
index, and if sarcopenia is present. The use of chemotherapy at half-maximal. Increasing the dosage increases the rate
will also increase the prevalence of cachexia. In Europe, the of receptor binding linearly until it reaches the maximal
US, and Japan, the 1-year mortality rate is 20 – 80%. Given binding rate (i.e., the V max ), which is the plateau of the
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that about 50% of cancer patients suffer from cachexia and hyperbolic curve.
the 20 – 80% 1-year mortality rate in these developed areas, 3. Mechanism of action of androgens in
10 – 40% of all cancer patients die of cachexia or cancer-
related muscle wasting. Our focus should be on the number skeletal muscle through the androgen
of cancer patients dying rather than solely on the prevalence receptor
of cachexia. A rough calculation based on cancer incidence Androgens bind to the androgen receptor in the cytoplasm
data in Europe (2018), the US (2022), and Japan (2022) of the cell; this complex then migrates into the nucleus
estimates that cancer cachexia is responsible for 391,000 and binds to DNA, inducing gene transcription in
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– 1,356,400 deaths in Europe, 238,019 – 952,076 deaths in skeletal muscles. Two notable deviations from the strict
the US, and 100,516 – 402,060 deaths in Japan. Even if the ligand (steroid) specificity occur when dosages shift from
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50% prevalence rate of cancer cachexia is a liberal estimate, physiological to pharmacological levels, as observed by
there are still at least 50,000 deaths from cancer cachexia Pihlajamaa et al. : (i) Pharmacological dosages produce
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in each of Europe, the US, and Japan, and this is not a more pronounced effects than physiological dosages, and
trivial problem. Therefore, cancer cachexia attenuation and (ii) different steroid structures exhibit varying affinities for
mitigation could save hundreds of thousands of lives in the androgen receptor, with some binding more effectively
each of these three geographical locations. This is an urgent than others. This prompts the research question: Can
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issue, and the repurposing of anabolic agents could help epigenetics affect the response to androgens? Through
stop or at least reduce these high mortality rates. It should both extranuclear and nuclear mechanisms, androgens
be noted that the diagnosis of cachexia is less important can activate or repress histone activity, thereby influencing
than treating it with anabolic agents. In no circumstances protein signaling. 10
would an increase in muscle mass be detrimental to a
cancer patient’s health, Grip strength is highly inversely 4. Mechanisms of action of androgens in
related to mortality in the elderly. Hence, it is proposed that breast tissue, prostate tissue, and other
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treating all cancer patients with an appropriate anabolic tissues during metastatic cancer
agent would increase life expectancy and reduce mortality
rates. Anabolic steroids or testosterone in non-androgen Steroid-hormone-receptor interactions recruit signaling
receptor-responsive tumors, and albuterol or other and/or scaffold proteins, stimulating flux through various
non-androgen receptor-binding anabolics in androgen pathways that promote cancer cell proliferation, survival,
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receptor-responsive tumors, should be considered the and migration for tissue invasion. Several scaffold
standard of care. In simple terms: treat the cancer cachexia proteins are as follows: (i) Steroid receptor co-activator-1
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and discontinue treatment during remission. (Src) is involved in androgen-induced prostate cancer
cell proliferation; (ii) integrins are membrane linkers
Anabolic therapies can and have been combined with
chemotherapy and radiotherapy in important clinical trials. across cell membranes that interact with the cytoskeleton
and extracellular matrix to induce metastasis and cell
This is crucial, as chemotherapy has been demonstrated to invasion; (iii) filamin A is a cytoskeleton protein that
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reduce muscle mass. 7
regulates androgen responsiveness through the androgen
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2. Pharmacodynamics explaining higher receptor and downregulates androgen receptor function;
response to pharmacological doses than (iv) PI3K is a signaling kinase (phosphorylates) that
is essential in insulin-signaling; and (v) P130 Cas is
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physiological doses of a drug involved in cell migration, apoptosis, and cell cycle
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The physiological and pharmacological molecular control. According to Giovannelli et al., the interaction
mechanisms that result in higher pharmacological of classical ligand-bound steroid receptors with scaffold
response to androgens compared to physiological doses and/or signaling proteins regulates cellular processes,
Volume 8 Issue 1 (2025) 76 doi: 10.36922/itps.4699