Monocarboxylate Transporter 1 Inhibitors as Potential Anticancer Agents

Abstract

Potent monocarboxylate transporter 1 inhibitors (MCT1) have been developed based on α-cyano-4-hydroxycinnamic acid template. Structure−activity relationship studies demonstrate that the introduction of p-N, N-dialkyl/diaryl, and o-methoxy groups into cyanocinnamic acid has maximal MCT1 inhibitory activity. Systemic toxicity studies in healthy ICR mice with few potent MCT1 inhibitors indicate normal body weight gains in treated animals. In vivo tumor growth inhibition studies in colorectal adenocarcinoma (WiDr cell line) in nude mice xenograft models establish that compound 27 exhibits single agent activity in inhibiting the tumor growth.

Coumarin carboxylic acids as monocarboxylate transporter 1 inhibitors: In vitro and in vivo studies as potential anticancer agents

“…23 This transport inhibition study revealed carboxy coumarins 4a – 4e as potent inhibitors of MCT1 at nanomolar to low micromolar concentrations (Table 1). …”

“…19–22 Elevated expression of MCT1 has been identified in a large number of cancers and, therefore, this transporter is a major selective target for broad-spectrum cancer treatment. 23–34 In this regard, we recently developed a series of MCT1 inhibitors based on the α-hydroxy-4-cyanocinnamic acid (CHC) template for potential anticancer applications. 23 Although our earlier CHC based MCT1 inhibitors are potent, the lead compounds suffer from poor oral bioavailability and toxicity at high concentrations.…”

“…23–34 In this regard, we recently developed a series of MCT1 inhibitors based on the α-hydroxy-4-cyanocinnamic acid (CHC) template for potential anticancer applications. 23 Although our earlier CHC based MCT1 inhibitors are potent, the lead compounds suffer from poor oral bioavailability and toxicity at high concentrations. In this regard, we envisioned to utilize a similar but bicyclic coumarin template to improve absorption, distribution, metabolism and elimination properties, decrease systemic toxicity and improve anticancer efficacy.…”

Two‐photon fluorescence lifetime imaging of intrinsic NADH in three‐dimensional tumor models

“…With respect to tumor-stromal cell interactions, a critically important discovery was the demonstration that tumor cells can induce neighboring stromal cells to become glycolytic and release high energy compounds that fuel malignant cell growth, a process called the "reverse Warburg effect." Due to these activities, compounds expressing efficient inhibition of MCTs have been proposed and studied as potential chemotherapeutic agents (8). In this case, these cancerassociated fibroblasts undergo aerobic glycolysis to produce pyruvate and lactate, which are then transported by monocarboxylate transporters (MCT1 and MCT4) to growing cancer cells for further adenosine triphosphate (ATP) synthesis by the tricarboxylic acid (TCA) cycle and OXPHOS (2,(4)(5)(6).…”

“…This stimulated production of new blood vessels can further support the proliferation of tumor cells by delivering oxygen and resources needed for cell growth. Due to these activities, compounds expressing efficient inhibition of MCTs have been proposed and studied as potential chemotherapeutic agents (8).…”