Recent Perspectives on Cardiovascular Toxicity Associated with Colorectal Cancer Drug Therapy

Abstract

Cardiotoxicity is a well-known adverse effect of cancer-related therapy that has a significant influence on patient outcomes and quality of life. The use of antineoplastic drugs to treat colorectal cancers (CRCs) is associated with a number of undesirable side effects including cardiac complications. For both sexes, CRC ranks second and accounts for four out of every ten cancer deaths. According to the reports, almost 39% of patients with colorectal cancer who underwent first-line chemotherapy suffered cardiovascular impairment. Although 5-fluorouracil is still the backbone of chemotherapy regimen for colorectal, gastric, and breast cancers, cardiotoxicity caused by 5-fluorouracil might affect anywhere from 1.5% to 18% of patients. The precise mechanisms underlying cardiotoxicity associated with CRC treatment are complex and may involve the modulation of various signaling pathways crucial for maintaining cardiac health including TKI ErbB2 or NRG-1, VEGF, PDGF, BRAF/Ras/Raf/MEK/ERK, and the PI3/ERK/AMPK/mTOR pathway, resulting in oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, ultimately damaging cardiac tissue. Thus, the identification and management of cardiotoxicity associated with CRC drug therapy while minimizing the negative impact have become increasingly important. The purpose of this review is to catalog the potential cardiotoxicities caused by anticancer drugs and targeted therapy used to treat colorectal cancer as well as strategies focused on early diagnosing, prevention, and treatment of cardiotoxicity associated with anticancer drugs used in CRC therapy.

Keywords: 5-fluorouracil; apoptosis; cardiotoxicity; chemotherapy; colorectal cancer; oxidative stress.

Figure 1

ABL Kinase Activation and Signaling in Solid Tumors. ABL kinases are activated by hyperactive receptor tyrosine kinases (RTKs), chemokine receptors, and SRC family kinases as well as by oxidative and metabolic stress. By activating multiple MMPs and actin-regulatory proteins such as RAC, cortactin, N-WASP, ABL interactor 1 (ABI1), and WAVE, activated ABL kinases promote cancer cell migration and invasion. ABL1 regulates cyclin D1 signaling downstream of the EPHB2 receptor to promote the activation of proliferative response factors in the intestinal epithelium and adenomas. In response to high fumarate levels, the ABL1 kinase becomes hyperactive in FH-deficient renal cancer cells (HLRCC); activated ABL1 promotes aerobic glycolysis via the mTOR-HIF1/pathway and also induces nuclear localization of the transcription factor NRF2 to induce the expression of NQO1 and other antioxidant response factors in HLRCC. NOTCH activation in the Apc⁺/D716 polyposis mouse intestinal epithelium promoted RBPJ-mediated transcription, leading to increased levels of DAB1, a substrate and activator of ABL kinases; activated ABL in colorectal cancer cells induced the tyrosine phosphorylation of TRIO on Y2681, leading to increased TRIO Rho-GEF activity.

Figure 2

Mechanism of action of ErbB2-targeted drugs. Panitumumab inhibits Domain II in HER-2, trastuzumab-induced heart failure, and the cardiomyopathy brought on by ErbB2 deletion have led many to the conclusion that trastuzumab induces cardiotoxicity by impeding the physiological functions of ErbB2 in the heart.

Figure 3

The VEGF inhibitors’ mechanisms of direct myocardial damage. The pro-apoptotic factor BAD may become active in response to the inhibition of ribosomal S6 kinase (RSK). As a result, BAX is activated, and the mitochondria release Cyt C.

Figure 4

Ras/Raf/MEK/ERK signaling pathway activation. It denotes a critical protein that is phosphorylation-controlled. Rtk, receptor tyrosine kinase, or RTK mammal son-of-sevenless; MAPK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; Shc, Src homology 2 domain-containing protein.

Figure 5

Mammalian target of rapamycin (mTOR) complexes (mTORCs) and the phosphoinositide 3-kinase (PI3K)/Akt signaling network. mTORC1 comprises regulatory-associated protein of mTOR (RAPTOR), proline-rich Akt substrate 40 kDa (PRAS40), mammalian lethal with Sec13 protein 8 (mLST8), and DEP domain-containing mTOR-interacting protein (DEPTOR), once TSC2 is phosphorylated by Akt, the GAP activity of the TSC1/TSC2 complex is repressed, allowing Rheb to accumulate in a GTP-bound state. As a consequence, Rheb–GTP upregulates the protein kinase activity of mTORC1. mTORC2 is involved in the spatial control of cell growth via cytoskeletal regulation.

Figure 6

Mechanism involved in relation to the cardiotoxicity caused by anthracyclines. The main contributors to the cardiotoxicity caused by anthracyclines are regulated by rho GTPases. Redox cycling and Fenton’s reaction are two ways that anthracyclines cause reactive oxygen species (ROS). ROS are the cause of inflammation and generate oxidative DNA damage. Anthracyclines also inhibit type II topoisomerases (TOP2), leading to extremely cytotoxic DNA double strand breaks (DSBs), which compel a pro-apoptotic DNA damage response and may ultimately cause cardiomyocyte cell death. RhoA and Rac1 engage in the regulation of the inflammatory process.

Figure 7

A schematic diagram of the possible mechanisms involved and protection from cardiovascular toxicity associated with colorectal cancer (CRC) drug therapy. (A) Anthracycline-induced cardiotoxicity and possible effect of dexrazoxane. (B) Beta blockers inhibit the sympathetic activity into cardiac cells and reduce the cardiac toxicity. (C) Mechanism involved in relation to the cardiotoxicity caused by anthracyclines and protection by ACE-I and angiotensin receptor blockers. (D) Aldosterone antagonist protection in cardiovascular toxicity associated in CRC drug therapy.