Lipid-Based Nanoparticle Formulation of Diallyl Trisulfide Chemosensitizes the Growth Inhibitory Activity of Doxorubicin in Colorectal Cancer Model: A Novel In Vitro, In Vivo and In Silico Analysis

Abstract

Garlic’s main bioactive organosulfur component, diallyl trisulfide (DATS), has been widely investigated in cancer models. However, DATS is not suitable for clinical use due to its low solubility. The current study seeks to improve DATS bioavailability and assess its chemopreventive and chemosensitizing properties in an AOM-induced colorectal cancer model. The polyethylene glycol coated Distearoylphosphatidylcholine/Cholesterol (DSPC/Chol) comprising DATS-loaded DATSL and doxorubicin (DOXO)-encapsulated DOXL liposomes was prepared and characterized. The changes in the sensitivity of DATS and DOXO by DATSL and DOXL were evaluated in RKO and HT-29 colon cancer cells. The synergistic effect of DATSL and DOXL was studied by cell proliferation assay in the combinations of IC10, IC25, and IC35 of DATSL with the IC10 of DOXL. AOM, DATSL, and DOXL were administered to different groups of mice for a period of 21 weeks. The data exhibited ~93% and ~46% entrapment efficiency of DATSL and DOXL, respectively. The size of sham liposomes was 110.5 nm, whereas DATSL and DOXL were 135.5 nm and 169 nm, respectively. DATSL and DOXL exhibited significant sensitivity in the cell proliferation experiment, lowering their IC50 doses by more than 8- and 14-fold, respectively. However, the DATSL IC10, IC25, and IC35 showed escalating chemosensitivity, and treated the cells in combination with DOXL IC10. Analysis of histopathological, cancer marker enzymes, and antioxidant enzymes revealed that the high dose of DATSL pretreatment and DOXL chemotherapy is highly effective in inhibiting AOM-induced colon cancer promotion. The combination of DATSL and DOXL indicated promise as a colorectal cancer treatment in this study. Intermolecular interactions of DATS and DOXO against numerous cancer targets by molecular docking indicated MMP-9 as the most favourable target for DATS exhibiting binding energy of −4.6 kcal/mol. So far, this is the first research to demonstrate the chemopreventive as well as chemosensitizing potential of DATSL in an animal model of colorectal cancer.

Aqueous Extract of Artemisia annua Shows In Vitro Antimicrobial Activity and an In Vivo Chemopreventive Effect in a Small-Cell Lung Cancer Model

“…The ABW from each group was recorded from week 0 and continuously monitored every 2 weeks for 22 weeks. The RLW was estimated using the formula below after sacrificing the animals from all groups, as described earlier [ 49 ]. The ABWs of the mice from each group were recorded every two weeks throughout the study.…”

Current Status and Emerging Trends in Colorectal Cancer Screening and Diagnostics

“…Additionally, molecular docking analysis identified potential interactions with cancer-related proteins, such as MMP-9, suggesting a mechanism for DATS action. This study presents a promising approach for colorectal cancer prevention and treatment, highlighting the potential of DATSL and DOXL as a novel and efficient therapeutic strategy [72].…”

“…The unique attributes of lipid-based nanoparticles, encompassing their biocompatibility, stability, and capacity to carry imaging payloads, render them well-suited for the precise and noninvasive diagnosis of CRC [71]. For instance, Alrumaihi et al [72] aimed to enhance the bioavailability of diallyl trisulfide (DATS), a bioactive compound with known anticancer properties, by encapsulating it in polyethylene glycol-coated liposomes (DATSL) and combining it with doxorubicin (DOXO)-encapsulated liposomes (DOXL). DATSL and DOXL exhibited significant sensitivity in inhibiting colon cancer cell proliferation, both individually and in combination, with a synergistic effect observed at specific concentration combinations, lowering the IC50 doses of DATS and DOXO by over 8-and 14-fold, respectively.…”

Organosulfur Compounds in Colorectal Cancer Prevention and Progression

“…DATS has also been demonstrated to be effective as a chemopreventive agent against CRC. One study found that DATS treatment at a concentration of 25 mg/kg body weight, three times per week via an unspecified route, significantly reduced tumor number and incidence in an AOM-induced CRC mouse model ( Table 1 ) [ 23 ]. Much like DADS, DATS is also hydrophobic and exhibits low bioavailability, limiting its potential for clinical use.…”

“…Another family of plant nutraceuticals are organosulfur compounds, such as diallyl trisulfide (DATS), methylsulfonylmethane, and isothiocyanates. They have been tested as antitumor or chemosensitizers in the co-therapy of CRC, due to their inhibition of matrix metalloproteases, inhibition of carcinogen activation enzymes, and induction of apoptosis [ 23 , 24 , 25 ]. In the human diet, these organosulfur compounds are present in vegetables such as garlic, onion, broccoli, cabbage, and others from those plant families ( Amaryllidaceae , Brassicaceae ) [ 26 , 27 ].…”