Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

Barreto, Rafael; Waning, David L.; Gao, Hongyu; Liu, Yunlong; Zimmers, Teresa A.; Bonetto, Andrea

doi:10.18632/oncotarget.9779

Cited by 160 publications

(314 citation statements)

References 73 publications

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“…These side effects are less likely to occur during less intensive maintenance treatment or observation 23. Furthermore, there is evidence from pre‐clinical and murine studies that oxaliplatin may promote skeletal muscle damage, for example, by targeting mitochondria 24, 25. Unfortunately, no data on lifestyle factors are available from the CAIRO3 study.…”

Section: Discussionmentioning

confidence: 99%

Impact of different palliative systemic treatments on skeletal muscle mass in metastatic colorectal cancer patients

Kurk

Peeters

Dorresteijn

et al. 2018

J cachexia sarcopenia muscle

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BackgroundObservational studies suggest that loss of skeletal muscle mass (SMM) is associated with chemotherapy‐related toxicity, poor quality of life, and poor survival in metastatic colorectal cancer (mCRC) patients. Little is known about the evolution of SMM during palliative systemic therapy. We investigated changes in SMM during various consecutive palliative systemic treatment regimens using repeated abdominal computed tomography scans of mCRC patients who participated in the randomized phase 3 CAIRO3 study.MethodsIn the CAIRO3 study, mCRC patients with stable disease or better after 6 cycles of first‐line treatment with capecitabine + oxaliplatin + bevacizumab (CAPOX‐B) were randomized between maintenance treatment with capecitabine + bevacizumab (CAP‐B) or observation. Upon first disease progression, in both groups, CAPOX‐B or other treatment was reintroduced until the second disease progression, which was the primary study endpoint. We analysed 1355 computed tomography scans of 450 (81%) CAIRO3 patients (64 ± 9.0 years, CAP‐B n = 223; observation n = 227) for SMM at four time points (i.e. prior to the start of pre‐randomization initial treatment, at randomization, and at first and at second disease progression) using the Slice‐o‐matic software and single slice evaluation at the lumbar 3 level. By using accepted and widely used formulas, whole body SMM was calculated. A linear mixed effects model, adjusted for relevant confounders, was used to assess SMM changes for the total group and within and between study arms.ResultsDuring 6 cycles of initial treatment with CAPOX‐B prior to randomization, SMM decreased significantly in all patients [CAP‐B arm: −0.53 kg (95% CI −1.12; −0.07) and observation arm: −0.85 kg (−1.45; −0.25)]. After randomization, SMM recovered during CAP‐B treatment by 1.32 kg (0.73; 1.90) and observation by 1.20 kg (0.63; 1.78) (median time from randomization to first disease progression 8.6 and 4.1 months for CAP‐B arm and observation arm, respectively). After first progression and during reintroduction treatment with CAPOX‐B or other treatment, SMM again decreased significantly and comparable in both arms, CAP‐B: −2.71 kg (−3.37; −2.03), and observation: −2.01 kg (−2.64; −1.41) (median time from first progression until second progression CAP‐B arm: 4.7 months and observation arm: 6.6 months).ConclusionsThis longitudinal study provides a unique insight in SMM changes in mCRC patients during palliative systemic treatment regimens, including observation. Our data show that muscle loss is reversible and may be influenced by the intensity of systemic regimens. Although studies have shown prognostic capacity for SMM, the effects of subsequent changes in SMM are unknown and may be clues for new future therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Impact of different palliative systemic treatments on skeletal muscle mass in metastatic colorectal cancer patients

Kurk

Peeters

Dorresteijn

et al. 2018

J cachexia sarcopenia muscle

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“…Along this line, we recently showed that therapies routinely used for the treatment of colorectal cancer play an important role in promoting muscle wasting and fatigue, particularly by affecting the muscle oxidative state and causing mitochondrial depletion (Barreto et al, 2016). Of note, significant loss of BMD was described in patients undergoing adjuvant chemotherapy for various gynecologic cancers (Christensen et al, 2016; Lee et al, 2016) or radiotherapy for abdominal tumors (Wei et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Despite all this, the identification of muscle-/bone-derived factors that may result into novel therapeutic targets for the treatment of sarcopenia and osteoporosis is far from being accomplished. Moreover, while it is largely accepted that strategies aimed at preserving muscle mass can improve survival and quality of life in cancer cachexia (Benny Klimek et al, 2010; Zhou et al, 2010), as well as tolerance to the anticancer therapies (Barreto et al, 2016; Hatakeyama et al, 2016), further studies will be required to clarify whether preserving bone mass in cachexia may represent a novel strategy to improve outcomes and survival in colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

et al. 2017

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Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.

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“…Muscle wasting reduces function, quality of life and decreases response to therapy. Low muscle mass increases chemotherapy toxicity, while chemotherapy in turn can cause muscle wasting and contribute to cachexia (Chen et al, 2015; Barreto et al, 2016; de Lima Junior et al, 2016; Toledo et al, 2016). Currently there are no approved, effective therapies for cachexia.…”

Section: Introductionmentioning

confidence: 99%

The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

Au¹,

Desai

Koniaris

et al. 2017

Front. Physiol.

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Cachexia, or wasting of skeletal muscle and fat, afflicts many patients with chronic diseases including cancer, organ failure, and AIDS. Muscle wasting reduces quality of life and decreases response to therapy. Cachexia is caused partly by elevated inflammatory cytokines, including interleukin-6 (IL-6). Others and we have shown that IL-6 alone is sufficient to induce cachexia both in vitro and in vivo. The mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor Selumetinib has been tested in clinical trials for various cancers. Moreover, Selumetinib has also been shown to inhibit the production of IL-6. In a retrospective analysis of a phase II clinical trial in advanced cholangiocarcinoma, patients treated with Selumetinib experienced significant gains in skeletal muscle vs. patients receiving standard therapy. However, the use of Selumetinib as a treatment for cachexia has yet to be investigated mechanistically. We sought to determine whether MEK inhibition could protect against cancer-induced cachexia in mice. In vitro, Selumetinib induced C2C12 myotube hypertrophy and nuclear accretion. Next we tested Selumetinib in the Lewis lung carcinoma (LLC) model of cancer cachexia. Treatment with Selumetinib reduced tumor mass and reduced circulating and tumor IL-6; however MEK inhibition did not preserve muscle mass. Similar wasting was seen in limb muscles of Selumetinib and vehicle-treated LLC mice, while greater fat and carcass weight loss was observed with Selumetinib treatment. As well, Selumetinib did not block wasting in C2C12 myotubes treated with LLC serum. Taken together, out results suggest that this MEK inhibitor is not protective in LLC cancer cachexia despite lowering IL-6 levels, and further that it might exacerbate tumor-induced weight loss. Differences from other studies might be disease, species or model-specific.

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Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

Cited by 160 publications

References 73 publications

Impact of different palliative systemic treatments on skeletal muscle mass in metastatic colorectal cancer patients

Impact of different palliative systemic treatments on skeletal muscle mass in metastatic colorectal cancer patients

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

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